U.S. patent application number 12/098353 was filed with the patent office on 2008-07-31 for system and methods for processing analyte sensor data.
This patent application is currently assigned to DexCom, Inc.. Invention is credited to James H. Brauker, Paul V. Goode, Apurv U. Kamath.
Application Number | 20080183399 12/098353 |
Document ID | / |
Family ID | 34120054 |
Filed Date | 2008-07-31 |
United States Patent
Application |
20080183399 |
Kind Code |
A1 |
Goode; Paul V. ; et
al. |
July 31, 2008 |
SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA
Abstract
Systems and methods for processing sensor analyte data,
including initiating calibration, updating calibration, evaluating
clinical acceptability of reference and sensor analyte data, and
evaluating the quality of sensor calibration. During initial
calibration, the analyte sensor data is evaluated over a period of
time to determine stability of the sensor. The sensor may be
calibrated using a calibration set of one or more matched sensor
and reference analyte data pairs. The calibration may be updated
after evaluating the calibration set for best calibration based on
inclusion criteria with newly received reference analyte data.
Fail-safe mechanisms are provided based on clinical acceptability
of reference and analyte data and quality of sensor calibration.
Algorithms provide for optimized prospective and retrospective
analysis of estimated blood analyte data from an analyte
sensor.
Inventors: |
Goode; Paul V.; (Cherry
Hill, NJ) ; Brauker; James H.; (Cement City, MI)
; Kamath; Apurv U.; (San Diego, CA) |
Correspondence
Address: |
KNOBBE, MARTENS, OLSEN & BEAR, LLP
2040 MAIN STREET, FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Assignee: |
DexCom, Inc.
San Diego
CA
|
Family ID: |
34120054 |
Appl. No.: |
12/098353 |
Filed: |
April 4, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11038340 |
Jan 18, 2005 |
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12098353 |
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10632537 |
Aug 1, 2003 |
6931327 |
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11038340 |
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Current U.S.
Class: |
702/22 |
Current CPC
Class: |
A61B 5/14532 20130101;
A61B 5/14865 20130101; A61B 5/1433 20130101; A61B 5/1495 20130101;
A61B 2562/085 20130101; A61B 5/1468 20130101; A61B 5/4839 20130101;
Y02A 90/10 20180101; A61B 2560/04 20130101; A61B 5/14546 20130101;
A61B 5/0031 20130101; A61B 2560/0223 20130101; A61B 5/150022
20130101; G01N 33/48707 20130101; A61B 5/743 20130101; A61B 5/1473
20130101 |
Class at
Publication: |
702/22 |
International
Class: |
G06F 19/00 20060101
G06F019/00 |
Claims
1. A method for validating of at least one of reference glucose
data and sensor glucose data, the method comprising: receiving
sensor data from a continuous glucose sensor, the sensor data
comprising one or more sensor data points; receiving reference data
from a reference glucose monitor, the reference data comprising one
or more reference data points; and validating at least one of the
one or more sensor data points and the one or more reference data
points.
2. The method of claim 1, further comprising a step of accepting
one or more reference data points as a valid entry, wherein the
step of validating is performed prior to the step of accepting one
or more sensor or reference data points as a valid entry.
3. The method of claim 1, further comprising a step of accepting
one or more reference data points for use in calibration of the
continuous glucose sensor, wherein the step of validating is
performed prior to the step of accepting one or more reference data
points for use in calibration.
4. The method of claim 1, wherein the step of validating comprises
determining if the one or more sensor or reference data points are
physiologically feasible based on one or more previous sensor or
one or more previous reference data points.
5. The method of claim 4, wherein physiologically feasibility is
based on at least one of a maximum rate of change of glucose
concentration in a host and a maximum acceleration of glucose
concentration in a host.
6. The method of claim 1, wherein the step of validating is based
on at least one of environmental information and physiological
information.
7. The method of claim 6, wherein the environmental information or
physiological information comprises information selected from the
group consisting of time of day, oxygen concentration, postural
effects, and patient-entered environmental data.
8. The method of claim 1, wherein the step of validating is based
on a determination of oxygen concentration.
9. The method of claim 1, further comprising a step of predicting
future glucose values, wherein the step of validating comprises
comparing a current glucose value to a time corresponding predicted
glucose value.
10. A system for validating of at least one of reference glucose
data and sensor glucose data, the system comprising: a sensor data
module configured to receive sensor data from a continuous glucose
sensor, the sensor data comprising one or more sensor data points;
a reference input module configured to receive reference data from
a reference glucose monitor, the reference data comprising one or
more reference data points; and a processor module configured to
validate at least one of the one or more sensor data points and the
one or more reference data points.
11. The system of claim 10, wherein the processor module is further
configured to accept at least one of one or more sensor data points
and one or more reference data points as a valid entry after
validating at least one of the one or more sensor data points and
the one or more reference data points.
12. The system of claim 10, wherein the processor module is further
configured to accept one or more reference data points for
calibrating after validating the one or more reference data
points.
13. The system of claim 10, wherein the processor module is
configured to validate the one or more sensor or reference data
points by determining if at least one of the one or more sensor
data points and the one or more reference data points are
physiologically feasible based on at least one of one or more
previous sensor data points and one or more previous reference data
points.
14. The system of claim 13, wherein physiologically feasibility is
based on at least one of a maximum rate of change of glucose
concentration in a host and a maximum acceleration of glucose
concentration in a host.
15. The system of claim 10, wherein the processor module is
configured to validate at least one of the one or more sensor data
points and one or more reference data points based on at least one
of environmental information and physiological information.
16. The system of claim 10, wherein the environmental information
or physiological information comprises information selected from
the group consisting of time of day, oxygen concentration, postural
effects, and patient-entered environmental data.
17. The system of claim 10, wherein the processor module is
configured to validate at least one of the one or more sensor
points and one or more reference data points based on a
determination of oxygen concentration.
18. The system of claim 10, wherein the processor module is further
configured to predict or to estimate a future one or more glucose
values based on previous sensor data, and wherein the processor
module is configured to validate at least one of the one or more
sensor data points and the one or more reference data points by
comparing a current glucose value to at least one of a time
corresponding predicted glucose value or an estimated glucose
value.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of Ser. No. 11/038,340
filed Jan. 18, 2005, which is a continuation of Ser. No.
10/632,537, filed Aug. 1, 2003. The disclosures of each of the
above-mentioned applications is hereby expressly incorporated by
reference in its entirety and is hereby expressly made a portion of
this application.
FIELD OF THE INVENTION
[0002] The present invention relates generally to systems and
methods for analyte sensor data processing. Particularly, the
present invention relates to retrospectively and/or prospectively
initiating a calibration, converting sensor data, updating the
calibration, evaluating received reference and sensor data, and
evaluating the calibration for the analyte sensor.
BACKGROUND OF THE INVENTION
[0003] Diabetes mellitus is a disorder in which the pancreas cannot
create sufficient insulin (Type I or insulin dependent) and/or in
which insulin is not effective (Type 2 or non-insulin dependent).
In the diabetic state, the victim suffers from high blood sugar,
which may cause an array of physiological derangements (e.g.,
kidney failure, skin ulcers, or bleeding into the vitreous of the
eye) associated with the deterioration of small blood vessels. A
hypoglycemic reaction (low blood sugar) may be induced by an
inadvertent overdose of insulin, or after a normal dose of insulin
or glucose-lowering agent accompanied by extraordinary exercise or
insufficient food intake.
[0004] Conventionally, a diabetic person carries a self-monitoring
blood glucose (SMBG) monitor, which typically comprises
uncomfortable finger pricking methods. Due to the lack of comfort
and convenience, a diabetic will normally only measure his or her
glucose level two to four times per day. Unfortunately, these time
intervals are so far spread apart that the diabetic will likely
find out too late, sometimes incurring dangerous side effects, of a
hyper- or hypo-glycemic condition. In fact, it is not only unlikely
that a diabetic will take a timely SMBG value, but the diabetic
will not know if their blood glucose value is going up (higher) or
down (lower) based on conventional methods, inhibiting their
ability to make educated insulin therapy decisions.
SUMMARY OF THE INVENTION
[0005] Systems and methods are needed that accurately provide
estimated glucose measurements to a diabetic patient continuously
and/or in real time so that they may proactively care for their
condition to safely avoid hyper- and hypo-glycemic conditions. Real
time and retrospective estimated glucose measurements require
reliable data processing in order to provide accurate and useful
output to a patient and/or doctor.
[0006] Similarly, systems and methods are needed that accurately
provide substantially continuous estimated analyte measurements for
a variety of known analytes (e.g., oxygen, salts, protein, and
vitamins) to provide prospective and/or retrospective data analysis
and output to a user.
[0007] Accordingly, systems and methods are provided for
retrospectively and/or prospectively calibrating a sensor,
initializing a sensor, converting sensor data into calibrated data,
updating and maintaining a calibration over time, evaluating
received reference and sensor data for clinical acceptability, and
evaluating the calibration statistical acceptability, to ensure
accurate and safe data output to a patient and/or doctor.
[0008] In a first embodiment a method is provided for initializing
a substantially continuous analyte sensor, the method including:
receiving a data stream from an analyte sensor, including one or
more sensor data points; receiving reference data from a reference
analyte monitor, including two or more reference data points;
providing at least two matched data pairs by matching reference
analyte data to substantially time corresponding sensor data;
forming a calibration set including the at least two matching data
pairs; and determining a stability of the continuous analyte
sensor.
[0009] In an aspect of the first embodiment, the step of
determining the stability of the substantially continuous analyte
sensor includes waiting a predetermined time period between about
one minute and about six weeks.
[0010] In an aspect of the first embodiment, the step of
determining the stability of the substantially continuous analyte
sensor includes evaluating at least two matched data pairs.
[0011] In an aspect of the first embodiment, the step of
determining the stability of the substantially continuous analyte
sensor includes evaluating one of pH, oxygen, hypochlorite,
interfering species, correlation of matched pairs, R-value,
baseline drift, baseline offset, and amplitude.
[0012] In an aspect of the first embodiment, the method further
includes providing one of an audible, visual, or tactile output to
a user based on the stability of the sensor.
[0013] In an aspect of the first embodiment, the step of providing
output based on the stability of the sensor includes indicating at
least one of a numeric estimated analyte value, a directional trend
of analyte concentration, and a graphical representation of an
estimated analyte value.
[0014] In an aspect of the first embodiment, the step of receiving
sensor data includes receiving sensor data from a substantially
continuous glucose sensor.
[0015] In an aspect of the first embodiment, the step of receiving
sensor data includes receiving sensor data from an implantable
glucose sensor.
[0016] In an aspect of the first embodiment, the step of receiving
sensor data includes receiving sensor data from subcutaneously
implantable glucose sensor.
[0017] In an aspect of the first embodiment, the step of receiving
reference data includes receiving reference data from a
self-monitoring blood glucose test.
[0018] In an aspect of the first embodiment, the step of receiving
reference data includes downloading reference data via a cabled
connection.
[0019] In an aspect of the first embodiment, the step of receiving
reference data includes downloading reference data via a wireless
connection.
[0020] In an aspect of the first embodiment, the step of receiving
reference data from a reference analyte monitor includes receiving
within a receiver internal communication from a reference analyte
monitor integral with the receiver.
[0021] In an aspect of the first embodiment, the step of forming a
calibration set includes evaluating at least one matched data pair
using inclusion criteria.
[0022] In an aspect of the first embodiment, the step of receiving
sensor data includes receiving sensor data that has been
algorithmically smoothed.
[0023] In an aspect of the first embodiment, the step of receiving
sensor data includes algorithmically smoothing the received sensor
data.
[0024] In an aspect of the first embodiment, the step of forming a
calibration set includes including in the calibration set between
one and six matched data pairs.
[0025] In an aspect of the first embodiment, the step of forming a
calibration set includes including six matched data pairs.
[0026] In an aspect of the first embodiment, the step of forming a
calibration set further includes determining a value for n, where n
is greater than one and represents the number of matched data pairs
in the calibration set.
[0027] In an aspect of the first embodiment, the step of
determining a value for n is determined as a function of the
frequency of the received reference data points and signal strength
over time.
[0028] In a second embodiment, a system is provided for
initializing a continuous analyte sensor, including: a sensor data
module operatively connected to a continuous analyte sensor that
receives a data stream including a plurality of time spaced sensor
data points from the analyte sensor; a reference input module
adapted to obtain reference data from a reference analyte monitor,
including one or more reference data points; a processor module
that forms one or more matched data pairs by matching reference
data to substantially time corresponding sensor data and
subsequently forms a calibration set including the one or more
matched data pairs; and a start-up module associated with the
processor module programmed to determine the stability of the
continuous analyte sensor.
[0029] In an aspect of the second embodiment, the sensor data
module is adapted to wirelessly receive sensor data points from the
sensor.
[0030] In an aspect of the second embodiment, the start-up module
is programmed to wait a predetermined time period between six hours
and six weeks.
[0031] In an aspect of the second embodiment, the start-up module
is programmed to evaluate at least two matched data pairs.
[0032] In an aspect of the second embodiment, the start-up module
is programmed to evaluate one of pH, oxygen, hypochlorite,
interfering species, correlation of matched pairs, R-value,
baseline drift, baseline offset, and amplitude.
[0033] In an aspect of the second embodiment, the system further
includes an output control module associated with the processor
module and programmed to control output of sensor data.
[0034] In an aspect of the second embodiment, the output control
module indicates at least one of a numeric estimated analyte value,
a directional trend of analyte concentration, and a graphical
representation of an estimated analyte value.
[0035] In an aspect of the second embodiment, the sensor data
module is configured to receive sensor data from substantially the
continuous glucose sensor.
[0036] In an aspect of the second embodiment, the sensor data
module is configured to receive sensor data from an implantable
glucose sensor.
[0037] In an aspect of the second embodiment, the sensor data
module is configured to receive sensor data from subcutaneously
implantable glucose sensor.
[0038] In an aspect of the second embodiment, the reference input
module is configured to receive reference data from a
self-monitoring blood glucose test.
[0039] In an aspect of the second embodiment, the reference input
module is configured to download reference data via a cabled
connection.
[0040] In an aspect of the second embodiment, the reference input
module is configured to download reference data via a wireless
connection.
[0041] In an aspect of the second embodiment, the system further
includes a reference analyte monitor integral with the system and
wherein the reference input module is configured to receive an
internal communication from the reference analyte monitor.
[0042] In an aspect of the second embodiment, the processor module
includes programming to evaluate at least one matched data pair
using inclusion criteria.
[0043] In an aspect of the second embodiment, the reference input
module is configured to receive sensor data that has been
algorithmically smoothed.
[0044] In an aspect of the second embodiment, the reference input
module is configured to algorithmically smooth the received sensor
data.
[0045] In an aspect of the second embodiment, the calibration set
includes between one and six matched data pairs.
[0046] In an aspect of the second embodiment, the calibration set
includes six matched data pairs.
[0047] In an aspect of the second embodiment, the calibration set
includes n matched data pairs, where n is greater than one.
[0048] In an aspect of the second embodiment, n is a function of
the frequency of the received reference data points and signal
strength over time.
[0049] In a third embodiment, a computer system is provided for
initializing a continuous analyte sensor, the computer system
including: a sensor data receiving module that receives sensor data
from the substantially continuous analyte sensor via a receiver,
including one or more sensor data points; a reference data
receiving module that receives reference data from a reference
analyte monitor, including one or more reference data points; a
data matching module that forms one or more matched data pairs by
matching reference data to substantially time corresponding sensor
data; a calibration set module that forms a calibration set
including at least one matched data pair; and a stability
determination module that determines the stability of the
continuous analyte sensor.
[0050] In an aspect of the third embodiment, the stability
determination module includes a system for waiting a predetermined
time period.
[0051] In an aspect of the third embodiment, the stability
determination module evaluates at least two matched data pairs.
[0052] In an aspect of the third embodiment, the stability
determination module evaluates one of pH, oxygen, hypochlorite,
interfering species, correlation of matched pairs, R-value,
baseline drift, baseline offset, and amplitude.
[0053] In an aspect of the third embodiment, the computer system
further includes an interface control module that provides output
to the user based on the stability of the sensor.
[0054] In an aspect of the third embodiment, the output from the
interface control module includes at least one of a numeric
estimated analyte value, an indication of directional trend of
analyte concentration, and a graphical representation of an
estimated analyte value.
[0055] In an aspect of the third embodiment, the reference data
receiving module is adapted to receive sensor data from a
substantially continuous glucose sensor.
[0056] In an aspect of the third embodiment, the reference data
receiving module is adapted to receive sensor data from an
implantable glucose sensor.
[0057] In an aspect of the third embodiment, the reference data
receiving module is adapted to receive sensor data from a
subcutaneously implantable glucose sensor.
[0058] In an aspect of the third embodiment, the reference data
receiving module is adapted to receive sensor data from a
self-monitoring blood glucose test.
[0059] In an aspect of the third embodiment, the reference data
receiving module is adapted to receive sensor data from a cabled
connection.
[0060] In an aspect of the third embodiment, the reference data
receiving module is adapted to download reference data via a
wireless connection.
[0061] In an aspect of the third embodiment, the reference data
receiving module is adapted to receive reference data from an
internal reference analyte monitor that is housed integrally the
computer system.
[0062] In an aspect of the third embodiment, the calibration set
module evaluates at least one matched data pair using inclusion
criteria.
[0063] In an aspect of the third embodiment, the sensor data
receiving module is adapted to receive sensor data that has been
algorithmically smoothed.
[0064] In an aspect of the third embodiment, the computer system
further includes a data smoothing module that smoothes the received
sensor data.
[0065] In an aspect of the third embodiment, the calibration set
module includes between one and six matched data pairs.
[0066] In an aspect of the third embodiment, the calibration set
module includes six matched data pairs.
[0067] In an aspect of the third embodiment, the calibration set
includes n number of matched data pairs, where n is greater than
one.
[0068] In an aspect of the third embodiment, n is a function of the
frequency of the received reference data points and signal strength
over time.
[0069] In a fourth embodiment, method is provided for initializing
a substantially continuous analyte sensor, the method including:
receiving sensor data from a substantially continuous analyte
sensor, including one or more sensor data points; receiving
reference data from a reference analyte monitor, including one or
more reference data points; forming one or more matched data pairs
by matching reference data to substantially time corresponding
sensor data; forming a calibration set including at least one
matched data pair; determining stability of continuous analyte
sensor; and outputting information reflective of the sensor data
once a predetermined level of stability has been determined.
[0070] In a fifth embodiment, a system is provided for initializing
a continuous analyte sensor, including: a sensor data module
operatively linked to a continuous analyte sensor and configured to
receive one or more sensor data points from the sensor; a reference
input module adapted to obtain one or more reference data points;
and a processor module associated with the sensor data module and
the input module and programmed to match reference data points with
time-matched sensor data points to form a calibration set including
at least one matched data pair; and a start-up module associated
with the processor module programmed to determine the stability of
the continuous analyte sensor and output information reflective of
the sensor data once a predetermined level of stability has been
determined.
[0071] In a sixth embodiment, a computer system is provided for
initializing a continuous analyte sensor, the system including: a
sensor data receiving module that receives sensor data including
one or more sensor data points from the substantially continuous
analyte sensor via a receiver; a reference data receiving module
for receiving reference data from a reference analyte monitor,
including one or more reference data points; a data matching module
for forming one or more matched data pairs by matching reference
data to substantially time corresponding sensor data; a calibration
set module for forming a calibration set including at least one
matched data pair; a stability determination module for evaluating
the stability of the continuous analyte sensor; and an interface
control module that outputs information reflective of the sensor
data once a predetermined level of stability has been
determined.
[0072] In a seventh embodiment, a method for initializing a glucose
sensor, the method including: receiving sensor data from the
glucose sensor, including one or more sensor data points; receiving
reference data from a reference glucose monitor, including one or
more reference data points; forming one or more matched data pairs
by matching reference data to substantially time corresponding
sensor data; determining whether the glucose sensor has reached a
predetermined level of stability.
[0073] In an eighth embodiment, a system is provided for
initializing a continuous analyte sensor, including: a sensor data
module operatively linked to a continuous analyte sensor and
configured to receive one or more sensor data points from the
sensor; a reference input module adapted to obtain one or more
reference data points; and a processor module associated with the
sensor data module and the input module and programmed to match
reference data points with time-matched sensor data points to form
a calibration set including at least one matched data pair; and a
stability module associated with the processor module programmed to
determine the stability of the continuous analyte sensor.
[0074] In a ninth embodiment, a method is provided for evaluating
clinical acceptability of at least one of reference and sensor
analyte data, the method including: receiving a data stream from an
analyte sensor, including one or more sensor data points; receiving
reference data from a reference analyte monitor, including one or
more reference data points; and evaluating the clinical
acceptability at least one of the reference and sensor analyte data
using substantially time corresponding reference or sensor data,
wherein the at least one of the reference and sensor analyte data
is evaluated for deviation from its substantially time
corresponding reference or sensor data and clinical risk associated
with that deviation based on the glucose value indicated by at
least one of the sensor and reference data.
[0075] In an aspect of the ninth embodiment, the method further
includes providing an output through a user interface responsive to
the clinical acceptability evaluation.
[0076] In an aspect of the ninth embodiment, the step of providing
an output includes alerting the user based on the clinical
acceptability evaluation.
[0077] In an aspect of the ninth embodiment, the step of providing
an output includes altering the user interface based on the
clinical acceptability evaluation.
[0078] In an aspect of the ninth embodiment, the step of altering
the user interface includes at least one of providing color-coded
information, trend information, directional information (e.g.,
arrows or angled lines), and/or fail-safe information.
[0079] In an aspect of the ninth embodiment, the step of evaluating
the clinical acceptability includes using one of a Clarke Error
Grid, a mean absolute difference calculation, a rate of change
calculation, a consensus grid, and a standard clinical acceptance
test.
[0080] In an aspect of the ninth embodiment, the method further
includes requesting additional reference data if the clinical
acceptability evaluation determines clinical unacceptability.
[0081] In an aspect of the ninth embodiment, the method further
includes repeating the clinical acceptability evaluation step for
the additional reference data.
[0082] In an aspect of the ninth embodiment, the method further
includes a step of matching reference data to substantially time
corresponding sensor data to form a matched pair after the clinical
acceptability evaluation step.
[0083] In a tenth embodiment, a system is provided for evaluating
clinical acceptability of at least one of reference and sensor
analyte data, the method including: means for receiving a data
stream from an analyte sensor, a plurality of time-spaced sensor
data points; means for receiving reference data from a reference
analyte monitor, including one or more reference data points; and
means for evaluating the clinical acceptability of at least one of
the reference and sensor analyte data using substantially time
corresponding reference and sensor data, wherein the at least one
of the reference and sensor analyte data is evaluated for deviation
from its substantially time corresponding reference or sensor data
and clinical risk associated with that deviation based on the
glucose value indicated by at least one of the sensor and reference
data.
[0084] In an aspect of the tenth embodiment, the system further
includes means for providing an output based through a user
interface responsive to the clinical acceptability evaluation.
[0085] In an aspect of the tenth embodiment, the means for
providing an output includes means for alerting the user based on
the clinical acceptability evaluation.
[0086] In an aspect of the tenth embodiment, the means for
providing an output includes means for altering the user interface
based on the clinical acceptability evaluation.
[0087] In an aspect of the tenth embodiment, the means for altering
the user interface includes at least one of providing color-coded
information, trend information, directional information (e.g.,
arrows or angled lines), and/or fail-safe information.
[0088] In an aspect of the tenth embodiment, the means for
evaluating the clinical acceptability includes using one of a
Clarke Error Grid, a mean absolute difference calculation, a rate
of change calculation, a consensus grid, and a standard clinical
acceptance test.
[0089] In an aspect of the tenth embodiment, the system further
includes means for requesting additional reference data if the
clinical acceptability evaluation determines clinical
unacceptability.
[0090] In an aspect of the tenth embodiment, the system further
includes means for repeated the clinical acceptability evaluation
for the additional reference data.
[0091] In an aspect of the tenth embodiment, the system further
includes means for matching reference data to substantially time
corresponding sensor data to form a matched data pair after the
clinical acceptability evaluation.
[0092] In an eleventh embodiment, a computer system is provided for
evaluating clinical acceptability of at least one of reference and
sensor analyte data, the computer system including: a sensor data
receiving module that receives a data stream including a plurality
of time spaced sensor data points from a substantially continuous
analyte sensor; a reference data receiving module that receives
reference data from a reference analyte monitor, including one or
more reference data points; and a clinical acceptability evaluation
module that evaluates at least one of the reference and sensor
analyte data using substantially time corresponding reference and
sensor data, wherein the at least one of the reference and sensor
analyte data is evaluated for deviation from its substantially time
corresponding reference or sensor data and clinical risk associated
with that deviation based on the glucose value indicated by at
least one of the sensor and reference data.
[0093] In an aspect of the eleventh embodiment, the computer system
further includes an interface control module that controls the user
interface based on the clinical acceptability evaluation.
[0094] In an aspect of the eleventh embodiment, the interface
control module alerts the user based on the clinical acceptability
evaluation.
[0095] In an aspect of the eleventh embodiment, the interface
control module alters the user interface based on the clinical
acceptability evaluation.
[0096] In an aspect of the eleventh embodiment, the interface
control module alters the user interface by providing at least one
of providing color-coded information, trend information,
directional information (e.g., arrows or angled lines), and/or
fail-safe information.
[0097] In an aspect of the eleventh embodiment, the clinical
acceptability evaluation module uses one of a Clarke Error Grid, a
mean absolute difference calculation, a rate of change calculation,
a consensus grid, and a standard clinical acceptance test to
evaluate clinical acceptability.
[0098] In an aspect of the eleventh embodiment, the interface
control module that requests additional reference data if the
clinical acceptability evaluation determines clinical
unacceptability.
[0099] In an aspect of the eleventh embodiment, the interface
control module evaluates the additional reference data using
clinical acceptability evaluation module.
[0100] In an aspect of the eleventh embodiment, the computer system
further includes a data matching module that matches clinically
acceptable reference data to substantially time corresponding
clinically acceptable sensor data to form a matched pair.
[0101] In a twelfth embodiment, a method is provided for evaluating
clinical acceptability of at least one of reference and sensor
analyte data, the method including: receiving a data stream from an
analyte sensor, including one or more sensor data points; receiving
reference data from a reference analyte monitor, including one or
more reference data points; evaluating the clinical acceptability
at least one of the reference and sensor analyte data using
substantially time corresponding reference and sensor data, wherein
the at least one of the reference and sensor analyte data is
evaluated for deviation from its substantially time corresponding
reference or sensor data and clinical risk associated with that
deviation based on the glucose value indicated by at least one of
the sensor and reference data; and providing an output through a
user interface responsive to the clinical acceptability
evaluation.
[0102] In an thirteenth embodiment, a method is provided for
evaluating clinical acceptability of at least one of reference and
sensor analyte data, the method including: receiving a data stream
from an analyte sensor, including one or more sensor data points;
receiving reference data from a reference analyte monitor,
including one or more reference data points; and evaluating the
clinical acceptability at least one of the reference and sensor
analyte data using substantially time corresponding reference and
sensor data, including using one of a Clarke Error Grid, a mean
absolute difference calculation, a rate of change calculation, and
a consensus grid.
[0103] In an fourteenth embodiment, a computer system is provided
for evaluating clinical acceptability of at least one of reference
and sensor analyte data, the computer system including: a sensor
data module that receives a data stream including a plurality of
time spaced sensor data points from a substantially continuous
analyte sensor; a reference input module that receives reference
data from a reference analyte monitor, including one or more
reference data points; a clinical module that evaluates at least
one of the reference and sensor analyte data using substantially
time corresponding reference and sensor data, wherein the at least
one of the reference and sensor analyte data is evaluated for
deviation from its substantially time corresponding reference or
sensor data and clinical risk associated with that deviation based
on the glucose value indicated by at least one of the sensor and
reference data; and an interface control module that controls the
user interface based on the clinical acceptability evaluation.
[0104] In an fifteenth embodiment, a computer system is provided
for evaluating clinical acceptability of at least one of reference
and sensor analyte data, the computer system including: a sensor
data module that receives a data stream including a plurality of
time spaced sensor data points from a substantially continuous
analyte sensor; a reference input module that receives reference
data from a reference analyte monitor, including one or more
reference data points; and a clinical module that evaluates at
least one of the reference and sensor analyte data with
substantially time corresponding reference and sensor data, wherein
the clinical module uses one of a Clarke Error Grid, a mean
absolute difference calculation, a rate of change calculation, a
consensus grid, and a standard clinical acceptance test to evaluate
clinical acceptability.
[0105] In an sixteenth embodiment, a computer system is provided
for evaluating clinical acceptability of at least one of reference
and sensor analyte data, the computer system including: a sensor
data module that receives a data stream including a plurality of
time spaced sensor data points from a substantially continuous
analyte sensor via a receiver; a reference input module that
receives reference data from a reference analyte monitor, including
one or more reference data points; and a clinical module that uses
a Clarke Error Grid to evaluate the clinical acceptability at least
one of the reference and sensor analyte data using substantially
time corresponding reference and sensor data; and a fail-safe
module that controls the user interface responsive to the clinical
module evaluating clinical unacceptability.
[0106] In an seventeenth embodiment, a method is provided for
evaluating clinical acceptability of at least one of reference and
sensor glucose data, the method including: receiving a data stream
from an analyte sensor, including one or more sensor data points;
receiving reference data from a reference glucose monitor,
including one or more reference data points; evaluating the
clinical acceptability at least one of the reference and sensor
glucose data using substantially time corresponding reference and
sensor data, wherein the at least one of the reference and sensor
analyte data is evaluated for deviation from its substantially time
corresponding reference or sensor data and clinical risk associated
with that deviation based on the glucose value indicated by at
least one of the sensor and reference data; and a fail-safe module
that controls the user interface responsive to the clinical module
evaluating clinical unacceptability.
[0107] In an eighteenth embodiment, a method is provided for
maintaining calibration of a substantially continuous analyte
sensor, the method including: receiving a data stream from an
analyte sensor, including one or more sensor data points; receiving
reference data from a reference analyte monitor, including two or
more reference data points; providing at least two matched data
pairs by matching reference analyte data to substantially time
corresponding sensor data; forming a calibration set including the
at least two matching data pairs; creating a conversion function
based on the calibration set; converting sensor data into
calibrated data using the conversion function; subsequently
obtaining one or more additional reference data points and creating
one or more new matched data pairs; evaluating the calibration set
when the new matched data pair is created, wherein evaluating the
calibration set includes at least one of 1) ensuring matched data
pairs in the calibration set span a predetermined time range, 2)
ensuring matched data pairs in the calibration set are no older
than a predetermined value, 3) ensuring the calibration set has
substantially distributed high and low matched data pairs over the
predetermined time range, and 4) allowing matched data pairs only
within a predetermined range of analyte values; and subsequently
modifying the calibration set if such modification is required by
the evaluation.
[0108] In an aspect of the eighteenth embodiment, the step of
evaluating the calibration set further includes at least one of
evaluating a rate of change of the analyte concentration,
evaluating a congruence of respective sensor and reference data in
the matched data pairs, and evaluating physiological changes.
[0109] In an aspect of the eighteenth embodiment, the step of
evaluating the calibration set includes evaluating only the new
matched data pair.
[0110] In an aspect of the eighteenth embodiment, the step of
evaluating the calibration set includes evaluating all of the
matched data pairs in the calibration set and the new matched data
pair.
[0111] In an aspect of the eighteenth embodiment, the step of
evaluating the calibration set includes evaluating combinations of
matched data pairs from the calibration set and the new matched
data pair.
[0112] In an aspect of the eighteenth embodiment, the step of
receiving sensor data includes receiving a data stream from a
long-term implantable analyte sensor.
[0113] In an aspect of the eighteenth embodiment, the step of
receiving sensor data includes receiving a data stream that has
been algorithmically smoothed.
[0114] In an aspect of the eighteenth embodiment, the step of
receiving sensor data stream includes algorithmically smoothing the
data stream.
[0115] In an aspect of the eighteenth embodiment, the step of
receiving reference data includes downloading reference data via a
cabled connection.
[0116] In an aspect of the eighteenth embodiment, the step of
receiving reference data includes downloading reference data via a
wireless connection.
[0117] In an aspect of the eighteenth embodiment, the step of
receiving reference data from a reference analyte monitor includes
receiving within a receiver internal communication from a reference
analyte monitor integral with the receiver.
[0118] In an aspect of the eighteenth embodiment, the reference
analyte monitor includes self-monitoring of blood analyte.
[0119] In an aspect of the eighteenth embodiment, the step of
creating a conversion function includes linear regression.
[0120] In an aspect of the eighteenth embodiment, the step of
creating a conversion function includes non-linear regression.
[0121] In an aspect of the eighteenth embodiment, the step of
forming a calibration set includes including in the calibration set
between one and six matched data pairs.
[0122] In an aspect of the eighteenth embodiment, the step of
forming a calibration set includes including six matched data
pairs.
[0123] In an aspect of the eighteenth embodiment, the step of
forming a calibration set further includes determining a value for
n, where n is greater than one and represents the number of matched
data pairs in the calibration set.
[0124] In an aspect of the eighteenth embodiment, the step of
determining a value for n is determined as a function of the
frequency of the received reference data points and signal strength
over time.
[0125] In an aspect of the eighteenth embodiment, the method
further includes determining a set of matching data pairs from the
evaluation of the calibration set and re-forming a calibration
set.
[0126] In an aspect of the eighteenth embodiment, the method
further includes repeating the step of re-creating the conversion
function using the re-formed calibration set.
[0127] In an aspect of the eighteenth embodiment, the method
further includes converting sensor data into calibrated data using
the re-created conversion function.
[0128] In a nineteenth embodiment, a system is provided for
maintaining calibration of a substantially continuous analyte
sensor, the system including: means for receiving a data stream
from an analyte sensor, a plurality of time-spaced sensor data
points; means for receiving reference data from a reference analyte
monitor, including two or more reference data points; means for
providing two or more matched data pairs by matching reference
analyte data to substantially time corresponding sensor data; means
for forming a calibration set including at least two matched data
pair; means for creating a conversion function based on the
calibration set; means for converting sensor data into calibrated
data using the conversion function; subsequently obtaining one or
more additional reference data points and creating one or more new
matched data pairs; means for evaluating the calibration set when
the new matched data pair is created, wherein evaluating the
calibration set includes at least one of 1) ensuring matched data
pairs in the calibration set span a predetermined time range, 2)
ensuring matched data pairs in the calibration set are no older
than a predetermined value, 3) ensuring the calibration set has
substantially distributed high and low matched data pairs over the
predetermined time range, and 4) allowing matched data pairs only
within a predetermined range of analyte values; and means for
modifying the calibration set if such modification is required by
the evaluation.
[0129] In an aspect of the nineteenth embodiment, the means for
evaluating the calibration set further includes at least one of
means for evaluating a rate of change of the analyte concentration,
means for evaluating a congruence of respective sensor and
reference data in matched data pairs; and means for evaluating
physiological changes.
[0130] In an aspect of the nineteenth embodiment, the means for
evaluating the calibration set includes means for evaluating only
the one or more new matched data pairs.
[0131] In an aspect of the nineteenth embodiment, the means for
evaluating the calibration set includes means for evaluating all of
the matched data pairs in the calibration set and the one or more
new matched data pairs.
[0132] In an aspect of the nineteenth embodiment, the means for
evaluating the calibration set includes means for evaluating
combinations of matched data pairs from the calibration set and the
one or more new matched data pair.
[0133] In an aspect of the nineteenth embodiment, the means for
receiving sensor data includes means for receiving sensor data from
a long-term implantable analyte sensor.
[0134] In an aspect of the nineteenth embodiment, the means for
receiving sensor data includes means for receiving sensor data that
has been algorithmically smoothed.
[0135] In an aspect of the nineteenth embodiment, the means for
receiving sensor data includes means for algorithmically smoothing
the receiving sensor data.
[0136] In an aspect of the nineteenth embodiment, the means for
receiving reference data includes means for downloading reference
data via a cabled connection.
[0137] In an aspect of the nineteenth embodiment, the means for
receiving reference data includes means for downloading reference
data via a wireless connection.
[0138] In an aspect of the nineteenth embodiment, the means for
receiving reference data from a reference analyte monitor includes
means for receiving within a receiver internal communication from a
reference analyte monitor integral with the receiver.
[0139] In an aspect of the nineteenth embodiment, the means for
receiving reference data includes means for receiving from a
self-monitoring of blood analyte.
[0140] In an aspect of the nineteenth embodiment, the means for
creating a conversion function includes means for performing linear
regression.
[0141] In an aspect of the nineteenth embodiment, the means for
creating a conversion function includes means for performing
non-linear regression.
[0142] In an aspect of the nineteenth embodiment, the means for
forming a calibration set includes including in the calibration set
between one and six matched data pairs.
[0143] In an aspect of the nineteenth embodiment, the means for
forming a calibration set includes including in the calibration set
six matched data pairs.
[0144] In an aspect of the nineteenth embodiment, the means for
forming a calibration set further includes determining a value for
n, where n is greater than one and represents the number of matched
data pairs in the calibration set.
[0145] In an aspect of the nineteenth embodiment, the means for
determining a value for n is determined as a function of the
frequency of the received reference data points and signal strength
over time.
[0146] In an aspect of the nineteenth embodiment, the system
further includes means for determining a set of matching data pairs
from the evaluation of the calibration set and re-forming a
calibration set.
[0147] In an aspect of the nineteenth embodiment, the system
further includes the means for repeating the set of creating the
conversion function using the re-formed calibration set.
[0148] In an aspect of the nineteenth embodiment, the system
further includes means for converting sensor data into calibrated
data using the re-created conversion function.
[0149] In a twentieth embodiment, a computer system is provided for
maintaining calibration of a substantially continuous analyte
sensor, the computer system including: a sensor data receiving
module that receives a data stream including a plurality of time
spaced sensor data points from a substantially continuous analyte
sensor; a reference data receiving module that receives reference
data from a reference analyte monitor, including two or more
reference data points; a data matching module that forms two or
more matched data pairs by matching reference data to substantially
time corresponding sensor data; a calibration set module that forms
a calibration set including at least two matched data pairs; a
conversion function module that creates a conversion function using
the calibration set; a sensor data transformation module that
converts sensor data into calibrated data using the conversion
function; and a calibration evaluation module that evaluates the
calibration set when the new matched data pair is provided, wherein
evaluating the calibration set includes at least one of 1) ensuring
matched data pairs in the calibration set span a predetermined time
period, 2) ensuring matched data pairs in the calibration set are
no older than a predetermined value, 3) ensuring the calibration
set has substantially distributed high and low matched data pairs
over a predetermined time range, and 4) allowing matched data pairs
only within a predetermined range of analyte values, wherein the
conversion function module is programmed to re-create the
conversion function of such modification is required by the
calibration evaluation module.
[0150] In an aspect of the twentieth embodiment, the evaluation
calibration module further evaluates at least one of a rate of
change of the analyte concentration, a congruence of respective
sensor and reference data in matched data pairs; and physiological
changes.
[0151] In an aspect of the twentieth embodiment, the evaluation
calibration module evaluates only the new matched data pair.
[0152] In an aspect of the twentieth embodiment, the evaluation
calibration module evaluates all of the matched data pairs in the
calibration set and the new matched data pair.
[0153] In an aspect of the twentieth embodiment, the evaluation
calibration module evaluates combinations of matched data pairs
from the calibration set and the new matched data pair.
[0154] In an aspect of the twentieth embodiment, the sensor data
receiving module receives the data stream from a long-term
implantable analyte sensor.
[0155] In an aspect of the twentieth embodiment, the sensor data
receiving module receives an algorithmically smoothed data
stream.
[0156] In an aspect of the twentieth embodiment, the sensor data
receiving module includes programming to smooth the data
stream.
[0157] In an aspect of the twentieth embodiment, the reference data
receiving module downloads reference data via a cabled
connection.
[0158] In an aspect of the twentieth embodiment, the reference data
receiving module downloads reference data via a wireless
connection.
[0159] In an aspect of the twentieth embodiment, the reference data
receiving module receives within a receiver internal communication
from a reference analyte monitor integral with the receiver.
[0160] In an aspect of the twentieth embodiment, the reference data
receiving module receives reference data from a self-monitoring of
blood analyte.
[0161] In an aspect of the twentieth embodiment, the conversion
function module includes programming that performs linear
regression.
[0162] In an aspect of the twentieth embodiment, the conversion
function module includes programming that performs non-linear
regression.
[0163] In an aspect of the twentieth embodiment, the calibration
set module includes in the calibration set between one and six
matched data pairs.
[0164] In an aspect of the twentieth embodiment, the calibration
set module includes in the calibration set six matched data
pairs.
[0165] In an aspect of the twentieth embodiment, the calibration
set module further includes programming for determining a value for
n, where n is greater than one and represents the number of matched
data pairs in the calibration set.
[0166] In an aspect of the twentieth embodiment, the programming
for determining a value for n determines n as a function of the
frequency of the received reference data points and signal strength
over time.
[0167] In an aspect of the twentieth embodiment, data matching
module further includes programming to re-form the calibration set
based on the calibration evaluation.
[0168] In an aspect of the twentieth embodiment, the conversion
function module further includes programming to re-create the
conversion function based on the re-formed calibration set.
[0169] In an aspect of the twentieth embodiment, the sensor data
transformation module further including programming for converting
sensor data into calibrated using the re-created conversion
function.
[0170] In a twenty-first embodiment, a method is provided for
maintaining calibration of a glucose sensor, the method including:
receiving a data stream from an analyte sensor, including one or
more sensor data points; receiving reference data from a reference
analyte monitor, including two or more reference data points;
providing at least two matched data pairs by matching reference
analyte data to substantially time corresponding sensor data;
forming a calibration set including the at least two matching data
pairs; creating a conversion function based on the calibration set;
subsequently obtaining one or more additional reference data points
and creating one or more new matched data pairs; and evaluating the
calibration set when the new matched data pair is created, wherein
evaluating the calibration set includes at least one of 1) ensuring
matched data pairs in the calibration set span a predetermined time
range, 2) ensuring matched data pairs in the calibration set are no
older than a predetermined value, 3) ensuring the calibration set
has substantially distributed high and low matched data pairs over
the predetermined time range, and 4) allowing matched data pairs
only within a predetermined range of analyte values.
[0171] In a twenty-second embodiment, a computer system is provided
for maintaining calibration of a glucose sensor, the computer
system including: a sensor data module that receives a data stream
including a plurality of time spaced sensor data points from a
substantially continuous analyte sensor; a reference input module
that receives reference data from a reference analyte monitor,
including two or more reference data points; a processor module
that forms two or more matched data pairs by matching reference
data to substantially time corresponding sensor data and
subsequently forms a calibration set including the two or more
matched data pairs; and a calibration evaluation module that
evaluates the calibration set when the new matched data pair is
provided, wherein evaluating the calibration set includes at least
one of 1) ensuring matched data pairs in the calibration set span a
predetermined time period, 2) ensuring matched data pairs in the
calibration set are no older than a predetermined value, 3)
ensuring the calibration set has substantially distributed high and
low matched data pairs over a predetermined time range, and 4)
allowing matched data pairs only within a predetermined range of
analyte values, wherein the conversion function module is
programmed to re-create the conversion function of such
modification is required by the calibration evaluation module.
[0172] In a twenty-third embodiment, a method is provided for
evaluating the quality of a calibration of an analyte sensor, the
method including: receiving a data stream from an analyte sensor,
including one or more sensor data points; receiving reference data
from a reference analyte monitor, including two or more reference
data points; providing at least two matched data pairs by matching
reference analyte data to substantially time corresponding sensor
data; forming a calibration set including the at least two matching
data pairs; creating a conversion function based on the calibration
set; receiving additional sensor data from the analyte sensor;
converting sensor data into calibrated data using the conversion
function; and evaluating the quality of the calibration set using a
data association function.
[0173] In an aspect of the twenty-third embodiment, the step of
receiving sensor data includes receiving a data stream that has
been algorithmically smoothed.
[0174] In an aspect of the twenty-third embodiment, the step of
receiving sensor data includes algorithmically smoothing the data
stream.
[0175] In an aspect of the twenty-third embodiment, the step of
receiving sensor data includes receiving sensor data from a
substantially continuous glucose sensor.
[0176] In an aspect of the twenty-third embodiment, the step of
receiving sensor data includes receiving sensor data from an
implantable glucose sensor.
[0177] In an aspect of the twenty-third embodiment, the step of
receiving sensor data includes receiving sensor data from a
subcutaneously implantable glucose sensor.
[0178] In an aspect of the twenty-third embodiment, the step of
receiving reference data includes receiving reference data from a
self-monitoring blood glucose test.
[0179] In an aspect of the twenty-third embodiment, the step of
receiving reference data includes downloading reference data via a
cabled connection.
[0180] In an aspect of the twenty-third embodiment, the step of
receiving reference data includes downloading reference data via a
wireless connection.
[0181] In an aspect of the twenty-third embodiment, the step of
receiving reference data from a reference analyte monitor includes
receiving within a receiver internal communication from a reference
analyte monitor integral with the receiver.
[0182] In an aspect of the twenty-third embodiment, the step of
evaluating the quality of the calibration set based on a data
association function includes performing one of linear regression,
non-linear regression, rank correlation, least mean square fit,
mean absolute deviation, and mean absolute relative difference.
[0183] In an aspect of the twenty-third embodiment, the step of
evaluating the quality of the calibration set based on a data
association function includes performing linear least squares
regression.
[0184] In an aspect of the twenty-third embodiment, the step of
evaluating the quality of the calibration set based on a data
association function includes setting a threshold of data
association.
[0185] In an aspect of the twenty-third embodiment, the step of
evaluating the quality of the calibration set based on data
association includes performing linear least squares regression and
wherein the step of setting a threshold hold includes an R-value
threshold of 0.79.
[0186] In an aspect of the twenty-third embodiment, the method
further includes providing an output to a user interface responsive
to the quality of the calibration set.
[0187] In an aspect of the twenty-third embodiment, the step of
providing an output includes displaying analyte values to a user
dependent upon the quality of the calibration.
[0188] In an aspect of the twenty-third embodiment, the step of
providing an output includes alerting the dependent upon the
quality of the calibration.
[0189] In an aspect of the twenty-third embodiment, the step of
providing an output includes altering the user interface dependent
upon the quality of the calibration.
[0190] In an aspect of the twenty-third embodiment, the step of
providing an output includes at least one of providing color-coded
information, trend information, directional information (e.g.,
arrows or angled lines), and/or fail-safe information.
[0191] In a twenty-fourth embodiment, a system is provided for
evaluating the quality of a calibration of an analyte sensor, the
system including: means for receiving a data stream from an analyte
sensor, a plurality of time-spaced sensor data points; means for
receiving reference data from a reference analyte monitor,
including two or more reference data points; means for providing
two or more matched data pairs by matching reference analyte data
to substantially time corresponding sensor data; means for forming
a calibration set including at least two matched data pair; means
for creating a conversion function based on the calibration set;
means for converting sensor data into calibrated data using the
conversion function; means for evaluating the quality of the
calibration set based on a data association function.
[0192] In an aspect of the twenty-fourth embodiment, the means for
receiving sensor data includes means for receiving sensor data that
has been algorithmically smoothed.
[0193] In an aspect of the twenty-fourth embodiment, the means for
receiving sensor data includes means for algorithmically smoothing
the receiving sensor data.
[0194] In an aspect of the twenty-fourth embodiment, the means for
receiving sensor data includes means for receiving sensor data from
substantially continuous glucose sensor.
[0195] In an aspect of the twenty-fourth embodiment, the means for
receiving sensor data includes means for receiving sensor data from
an implantable glucose sensor.
[0196] In an aspect of the twenty-fourth embodiment, the means for
receiving sensor data includes means for receiving sensor data from
subcutaneously implantable glucose sensor.
[0197] In an aspect of the twenty-fourth embodiment, the means for
receiving reference data includes means for receiving reference
data from a self-monitoring blood glucose test.
[0198] In an aspect of the twenty-fourth embodiment, the means for
receiving reference data includes means for downloading reference
data via a cabled connection.
[0199] In an aspect of the twenty-fourth embodiment, the means for
receiving reference data includes means for downloading reference
data via a wireless connection.
[0200] In an aspect of the twenty-fourth embodiment, the means for
receiving reference data from a reference analyte monitor includes
means for receiving within a receiver internal communication from a
reference analyte monitor integral with the receiver.
[0201] In an aspect of the twenty-fourth embodiment, the means for
evaluating the quality of the calibration set includes means for
performing one of linear regression, non-linear regression, rank
correlation, least mean square fit, mean absolute deviation, and
mean absolute relative difference.
[0202] In an aspect of the twenty-fourth embodiment, the means for
evaluating the quality of the calibration set includes means for
performing linear least squares regression.
[0203] In an aspect of the twenty-fourth embodiment, the means for
evaluating the quality of the calibration set includes means for
setting a threshold of data association.
[0204] In an aspect of the twenty-fourth embodiment, the means for
evaluating the quality of the calibration set includes means for
performing linear least squares regression and wherein the means
for setting a threshold hold includes an R-value threshold of
0.71.
[0205] In an aspect of the twenty-fourth embodiment, the system
further includes means for providing an output to a user interface
responsive to the quality of the calibration set.
[0206] In an aspect of the twenty-fourth embodiment, the means for
providing an output includes means for displaying analyte values to
a user dependent upon the quality of the calibration.
[0207] In an aspect of the twenty-fourth embodiment, the means for
providing an output includes means for alerting the dependent upon
the quality of the calibration.
[0208] In an aspect of the twenty-fourth embodiment, the means for
providing an output includes means for altering the user interface
dependent upon the quality of the calibration.
[0209] In an aspect of the twenty-fourth embodiment, the means for
providing an output includes at least one of providing color-coded
information, trend information, directional information (e.g.,
arrows or angled lines), and/or fail-safe information.
[0210] In a twenty-fifth embodiment, a computer system is provided
for evaluating the quality of a calibration of an analyte sensor,
the computer system including: a sensor data receiving module that
receives a data stream including a plurality of time spaced sensor
data points from a substantially continuous analyte sensor; a
reference data receiving module that receives reference data from a
reference analyte monitor, including two or more reference data
points; a data matching module that forms two or more matched data
pairs by matching reference data to substantially time
corresponding sensor data; a calibration set module that forms a
calibration set including at least two matched data pairs; a
conversion function module that creates a conversion function using
the calibration set; a sensor data transformation module that
converts sensor data into calibrated data using the conversion
function; and a quality evaluation module that evaluates the
quality of the calibration set based on a data association
function.
[0211] In an aspect of the twenty-fifth embodiment, the sensor data
receiving module receives sensor data that has been algorithmically
smoothed.
[0212] In an aspect of the twenty-fifth embodiment, the computer
system further includes a data smoothing module that
algorithmically smoothes sensor data received from the sensor data
receiving module.
[0213] In an aspect of the twenty-fifth embodiment, the sensor data
receiving module is adapted to receive sensor data from
substantially continuous glucose sensor.
[0214] In an aspect of the twenty-fifth embodiment, the sensor data
receiving module is adapted to receive sensor data from an
implantable glucose sensor.
[0215] In an aspect of the twenty-fifth embodiment, the sensor data
receiving module is adapted to receive sensor data from
subcutaneously implantable glucose sensor.
[0216] In an aspect of the twenty-fifth embodiment, the reference
data receiving module is adapted to receive reference data from a
self-monitoring blood glucose test.
[0217] In an aspect of the twenty-fifth embodiment, the reference
data receiving module is adapted to download reference data via a
cabled connection.
[0218] In an aspect of the twenty-fifth embodiment, the reference
data receiving module is adapted to download reference data via a
wireless connection.
[0219] In an aspect of the twenty-fifth embodiment, the reference
data receiving module is adapted to receive reference data from a
reference analyte monitor integral with the receiver.
[0220] In an aspect of the twenty-fifth embodiment, the quality
evaluation module performs one of linear regression, non-linear
regression, rank correlation, least mean square fit, mean absolute
deviation, and mean absolute relative difference to evaluate
calibration set quality.
[0221] In an aspect of the twenty-fifth embodiment, the quality
evaluation module performs linear least squares regression.
[0222] In an aspect of the twenty-fifth embodiment, the quality
evaluation module sets a threshold for the data association
function.
[0223] In an aspect of the twenty-fifth embodiment, the quality
evaluation module performs linear least squares regression and
wherein the threshold of the data association function includes an
R-value threshold of at least 0.79.
[0224] In an aspect of the twenty-fifth embodiment, the computer
system further includes an interface control module that controls
the user interface based on the quality of the calibration set.
[0225] In an aspect of the twenty-fifth embodiment, the interface
control module displays analyte values to a user dependent upon the
quality of the calibration set.
[0226] In an aspect of the twenty-fifth embodiment, the interface
control module alerts the user based upon the quality of the
calibration set.
[0227] In an aspect of the twenty-fifth embodiment, the interface
control module alters the user interface based upon the quality of
the calibration set.
[0228] In an aspect of the twenty-fifth embodiment, the interface
control module provides at least one of color-coded information,
trend information, directional information (e.g., arrows or angled
lines), and/or fail-safe information.
[0229] In a twenty-sixth embodiment, a method is provided for
evaluating the quality of a calibration of an analyte sensor, the
method including: receiving a data stream from an analyte sensor,
including one or more sensor data points; receiving reference data
from a reference analyte monitor, including two or more reference
data points; providing at least two matched data pairs by matching
reference analyte data to substantially time corresponding sensor
data; forming a calibration set including the at least two matching
data pairs; creating a conversion function based on the calibration
set; receiving additional sensor data from the analyte sensor;
converting sensor data into calibrated data using the conversion
function; and evaluating the quality of the calibration set based
on a data association function selected from the group consisting
of linear regression, non-linear regression, rank correlation,
least mean square fit, mean absolute deviation, and mean absolute
relative difference.
[0230] In a twenty-seventh embodiment, a method is provided for
evaluating the quality of a calibration of an analyte sensor, the
method including: receiving a data stream from an analyte sensor,
including one or more sensor data points; receiving reference data
from a reference analyte monitor, including two or more reference
data points; providing at least two matched data pairs by matching
reference analyte data to substantially time corresponding sensor
data; forming a calibration set including the at least two matching
data pairs; creating a conversion function based on the calibration
set; receiving additional sensor data from the analyte sensor;
converting sensor data into calibrated data using the conversion
function; evaluating the quality of the calibration set using a
data association function; and providing an output to a user
interface responsive to the quality of the calibration set.
[0231] In a twenty-eighth embodiment, a computer system is provided
for evaluating the quality of a calibration of an analyte sensor,
the computer system including: a sensor data module that receives a
data stream including a plurality of time spaced sensor data points
from a substantially continuous analyte sensor; a reference input
module that receives reference data from a reference analyte
monitor, including two or more reference data points; a processor
module that forms two or more matched data pairs by matching
reference data to substantially time corresponding sensor data and
subsequently forms a calibration set including the two or more
matched data pairs; and a conversion function module that creates a
conversion function using the calibration set; a sensor data
transformation module that converts sensor data into calibrated
data using the conversion function; a quality evaluation module
that evaluates the quality of the calibration set based on a data
association selected from the group consisting of linear
regression, non-linear regression, rank correlation, least mean
square fit, mean absolute deviation, and mean absolute relative
difference.
[0232] In a twenty-ninth embodiment, a computer system is provided
for evaluating the quality of a calibration of an analyte sensor,
the computer system including: a sensor data module that receives a
data stream including a plurality of time spaced sensor data points
from a substantially continuous analyte sensor; a reference input
module that receives reference data from a reference analyte
monitor, including two or more reference data points; a processor
module that forms two or more matched data pairs by matching
reference data to substantially time corresponding sensor data and
subsequently forms a calibration set including the two or more
matched data pairs; and a conversion function module that creates a
conversion function using the calibration set; a sensor data
transformation module that converts sensor data into calibrated
data using the conversion function; a quality evaluation module
that evaluates the quality of the calibration set based on data
association; and a fail-safe module that controls the user
interface based on the quality of the calibration set.
[0233] In a thirtieth embodiment, a method is provided for
evaluating the quality of a calibration of a glucose sensor, the
method including: receiving sensor data from a glucose sensor,
including one or more sensor data points; receiving reference data
from a reference glucose monitor, including one or more reference
data points; providing one or more matched data pairs by matched
reference glucose data to substantially time corresponding sensor
data; forming a calibration set including at least one matched data
pair; and evaluating the quality of the calibration set based on
data association.
BRIEF DESCRIPTION OF THE DRAWINGS
[0234] FIG. 1 is an exploded perspective view of a glucose sensor
in one embodiment.
[0235] FIG. 2 is a block diagram that illustrates the sensor
electronics in one embodiment.
[0236] FIG. 3 is a graph that illustrates data smoothing of a raw
data signal in one embodiment.
[0237] FIGS. 4A to 4D are schematic views of a receiver in first,
second, third, and fourth embodiments, respectively.
[0238] FIG. 5 is a block diagram of the receiver electronics in one
embodiment.
[0239] FIG. 6 is a flow chart that illustrates the initial
calibration and data output of the sensor data in one
embodiment.
[0240] FIG. 7 is a graph that illustrates a regression performed on
a calibration set to obtain a conversion function in one exemplary
embodiment.
[0241] FIG. 8 is a flow chart that illustrates the process of
evaluating the clinical acceptability of reference and sensor data
in one embodiment.
[0242] FIG. 9 is a graph of two data pairs on a Clarke Error Grid
to illustrate the evaluation of clinical acceptability in one
exemplary embodiment.
[0243] FIG. 10 is a flow chart that illustrates the process of
evaluation of calibration data for best calibration based on
inclusion criteria of matched data pairs in one embodiment.
[0244] FIG. 11 is a flow chart that illustrates the process of
evaluating the quality of the calibration in one embodiment.
[0245] FIGS. 12A and 12B are graphs that illustrate an evaluation
of the quality of calibration based on data association in one
exemplary embodiment using a correlation coefficient.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0246] The following description and examples illustrate some
exemplary embodiments of the disclosed invention in detail. Those
of skill in the art will recognize that there are numerous
variations and modifications of this invention that are encompassed
by its scope. Accordingly, the description of a certain exemplary
embodiment should not be deemed to limit the scope of the present
invention.
DEFINITIONS
[0247] In order to facilitate an understanding of the disclosed
invention, a number of terms are defined below.
[0248] The term "analyte," as used herein, is a broad term and is
used in its ordinary sense, including, without limitation, to refer
to a substance or chemical constituent in a biological fluid (for
example, blood, interstitial fluid, cerebral spinal fluid, lymph
fluid or urine) that can be analyzed. Analytes may include
naturally occurring substances, artificial substances, metabolites,
and/or reaction products. In some embodiments, the analyte for
measurement by the sensor heads, devices, and methods is analyte.
However, other analytes are contemplated as well, including but not
limited to acarboxyprothrombin; acylcarnitine; adenine
phosphoribosyl transferase; adenosine deaminase; albumin;
alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle),
histidine/urocanic acid, homocysteine, phenylalanine/tyrosine,
tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers;
arginase; benzoylecgonine (cocaine); biotinidase; biopterin;
c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin;
chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase;
conjugated 1-.beta. hydroxy-cholic acid; cortisol; creatine kinase;
creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine;
de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA
(acetylator polymorphism, alcohol dehydrogenase, alpha
1-antitrypsin, cystic fibrosis, Duchenne/Becker muscular dystrophy,
analyte-6-phosphate dehydrogenase, hemoglobinopathies, A,S,C,E,
D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1,
Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium
vivax, sexual differentiation, 21-deoxycortisol);
desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanus
antitoxin; erythrocyte arginase; erythrocyte protoporphyrin;
esterase D; fatty acids/acylglycines; free .beta.-human chorionic
gonadotropin; free erythrocyte porphyrin; free thyroxine (FT4);
free tri-iodothyronine (FT3); fumarylacetoacetase;
galactose/gal-1-phosphate; galactose-1-phosphate uridyltransferase;
gentamicin; analyte-6-phosphate dehydrogenase; glutathione;
glutathione perioxidase; glycocholic acid; glycosylated hemoglobin;
halofantrine; hemoglobin variants; hexosaminidase A; human
erythrocyte carbonic anhydrase I; 17 alpha-hydroxyprogesterone;
hypoxanthine phosphoribosyl transferase; immunoreactive trypsin;
lactate; lead; lipoproteins ((a), B/A-1, .beta.); lysozyme;
mefloquine; netilmicin; phenobarbitone; phenytoin;
phytanic/pristanic acid; progesterone; prolactin; prolidase; purine
nucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);
selenium; serum pancreatic lipase; sissomicin; somatomedin C;
specific antibodies (adenovirus, anti-nuclear antibody, anti-zeta
antibody, arbovirus, Aujeszky's disease virus, dengue virus,
Dracunculus medinensis, Echinococcus granulosus, Entamoeba
histolytica, enterovirus, Giardia duodenalisa, Helicobacter pylori,
hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease),
influenza virus, Leishmania donovani, leptospira,
measles/mumps/rubella, Mycobacterium leprae, Mycoplasma pneumoniae,
Myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodium
falciparum, poliovirus, Pseudomonas aeruginosa, respiratory
syncytial virus, rickettsia (scrub typhus), Schistosoma mansoni,
Toxoplasma gondii, Trepenoma pallidium, Trypanosoma cruzi/rangeli,
vesicular stomatis virus, Wuchereria bancrofti, yellow fever
virus); specific antigens (hepatitis B virus, HIV-1);
succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH);
thyroxine (T4); thyroxine-binding globulin; trace elements;
transferrin; UDP-galactose-4-epimerase; urea; uroporphyrinogen I
synthase; vitamin A; white blood cells; and zinc protoporphyrin.
Salts, sugar, protein, fat, vitamins and hormones naturally
occurring in blood or interstitial fluids may also constitute
analytes in certain embodiments. The analyte may be naturally
present in the biological fluid, for example, a metabolic product,
a hormone, an antigen, an antibody, and the like. Alternatively,
the analyte may be introduced into the body, for example, a
contrast agent for imaging, a radioisotope, a chemical agent, a
fluorocarbon-based synthetic blood, or a drug or pharmaceutical
composition, including but not limited to insulin; ethanol;
cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants
(nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons,
hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines,
methamphetamines, Ritalin, Cylert, Preludin, Didrex, PreState,
Voranil, Sandrex, Plegine); depressants (barbituates, methaqualone,
tranquilizers such as Valium, Librium, Miltown, Serax, Equanil,
Tranxene); hallucinogens (phencyclidine, lysergic acid, mescaline,
peyote, psilocybin); narcotics (heroin, codeine, morphine, opium,
meperidine, Percocet, Percodan, Tussionex, Fentanyl, Darvon,
Talwin, Lomotil); designer drugs (analogs of fentanyl, meperidine,
amphetamines, methamphetamines, and phencyclidine, for example,
Ecstasy); anabolic steroids; and nicotine. The metabolic products
of drugs and pharmaceutical compositions are also contemplated
analytes. Analytes such as neurochemicals and other chemicals
generated within the body may also be analyzed, such as, for
example, ascorbic acid, uric acid, dopamine, noradrenaline,
3-methoxytyramine (3MT), 3,4-Dihydroxyphenylacetic acid (DOPAC),
Homovanillic acid (HVA), 5-Hydroxytryptamine (5HT), and
5-Hydroxyindoleacetic acid (FHIAA).
[0249] The terms "operably connected" and "operably linked," as
used herein, are broad terms and are used in their ordinary sense,
including, without limitation, one or more components being linked
to another component(s) in a manner that allows transmission of
signals between the components, e.g., wired or wirelessly. For
example, one or more electrodes may be used to detect the amount of
analyte in a sample and convert that information into a signal; the
signal may then be transmitted to an electronic circuit means. In
this case, the electrode is "operably linked" to the electronic
circuitry.
[0250] The term "EEPROM," as used herein, is a broad term and is
used in its ordinary sense, including, without limitation,
electrically erasable programmable read-only memory, which is
user-modifiable read-only memory (ROM) that can be erased and
reprogrammed (e.g., written to) repeatedly through the application
of higher than normal electrical voltage.
[0251] The term "SRAM," as used herein, is a broad term and is used
in its ordinary sense, including, without limitation, static random
access memory (RAM) that retains data bits in its memory as long as
power is being supplied.
[0252] The term "A/D Converter," as used herein, is a broad term
and is used in its ordinary sense, including, without limitation,
hardware that converts analog signals into digital signals.
[0253] The term "microprocessor," as used herein, is a broad term
and is used in its ordinary sense, including, without limitation a
computer system or processor designed to perform arithmetic and
logic operations using logic circuitry that responds to and
processes the basic instructions that drive a computer.
[0254] The term "RF transceiver," as used herein, is a broad term
and is used in its ordinary sense, including, without limitation, a
radio frequency transmitter and/or receiver for transmitting and/or
receiving signals.
[0255] The term "jitter" as used herein, is a broad term and is
used in its ordinary sense, including, without limitation,
uncertainty or variability of waveform timing, which may be cause
by ubiquitous noise caused by a circuit and/or environmental
effects; jitter can be seen in amplitude, phase timing, or the
width of the signal pulse.
[0256] The term "raw data signal," as used herein, is a broad term
and is used in its ordinary sense, including, without limitation,
an analog or digital signal directly related to the measured
analyte from the analyte sensor. In one example, the raw data
signal is digital data in "counts" converted by an A/D converter
from an analog signal (e.g., voltage or amps) representative of an
analyte concentration.
[0257] The term "counts," as used herein, is a broad term and is
used in its ordinary sense, including, without limitation, a unit
of measurement of a digital signal. In one example, a raw data
signal measured in counts is directly related to a voltage
(converted by an A/D converter), which is directly related to
current.
[0258] The term "analyte sensor," as used herein, is a broad term
and is used in its ordinary sense, including, without limitation,
any mechanism (e.g. enzymatic or non-enzymatic) by which analyte
can be quantified. For example, some embodiments utilize a membrane
that contains glucose oxidase that catalyzes the conversion of
oxygen and glucose to hydrogen peroxide and gluconate:
Glucose+O.sub.2.fwdarw.Gluconate+H.sub.2O.sub.2
[0259] Because for each glucose molecule metabolized, there is a
proportional change in the co-reactant .degree. 2 and the product
H.sub.2O.sub.2, one can use an electrode to monitor the current
change in either the co-reactant or the product to determine
glucose concentration.
[0260] The term "host," as used herein, is a broad term and is used
in its ordinary sense, including, without limitation, mammals,
particularly humans.
[0261] The term "matched data pairs", as used herein, is a broad
term and is used in its ordinary sense, including, without
limitation, reference data (e.g., one or more reference analyte
data points) matched with substantially time corresponding sensor
data (e.g., one or more sensor data points).
[0262] The term "Clarke Error Grid", as used herein, is a broad
term and is used in its ordinary sense, including, without
limitation, an error grid analysis, which evaluates the clinical
significance of the difference between a reference glucose value
and a sensor generated glucose value, taking into account 1) the
value of the reference glucose measurement, 2) the value of the
sensor glucose measurement, 3) the relative difference between the
two values, and 4) the clinical significance of this difference.
See Clarke et al., "Evaluating Clinical Accuracy of Systems for
Self-Monitoring of Blood Glucose", Diabetes Care, Volume 10, Number
5, September-October 1987, which is incorporated by reference
herein in its entirety.
[0263] The term "Consensus Error Grid", as used herein, is a broad
term and is used in its ordinary sense, including, without
limitation, an error grid analysis that assigns a specific level of
clinical risk to any possible error between two time corresponding
glucose measurements. The Consensus Error Grid is divided into
zones signifying the degree of risk posed by the deviation. See
Parkes et al., "A New Consensus Error Grid to Evaluate the Clinical
Significance of Inaccuracies in the Measurement of Blood Glucose",
Diabetes Care, Volume 23, Number 8, August 2000, which is
incorporated by reference herein in its entirety.
[0264] The term "clinical acceptability", as used herein, is a
broad term and is used in its ordinary sense, including, without
limitation, determination of the risk of inaccuracies to a patient.
Clinical acceptability considers a deviation between time
corresponding glucose measurements (e.g., data from a glucose
sensor and data from a reference glucose monitor) and the risk
(e.g., to the decision making of a diabetic patient) associated
with that deviation based on the glucose value indicated by the
sensor and/or reference data. One example of clinical acceptability
may be 85% of a given set of measured analyte values within the "A"
and "B" region of a standard Clarke Error Grid when the sensor
measurements are compared to a standard reference measurement.
[0265] The term "R-value," as used herein, is a broad term and is
used in its ordinary sense, including, without limitation, one
conventional way of summarizing the correlation of data; that is, a
statement of what residuals (e.g., root mean square deviations) are
to be expected if the data are fitted to a straight line by the a
regression.
[0266] The term "data association" and "data association function,"
as used herein, are a broad terms and are used in their ordinary
sense, including, without limitation, a statistical analysis of
data and particularly its correlation to, or deviation from, from a
particular curve. A data association function is used to show data
association. For example, the data that forms that calibration set
as described herein may be analyzed mathematically to determine its
correlation to, or deviation from, a curve (e.g., line or set of
lines) that defines the conversion function; this correlation or
deviation is the data association. A data association function is
used to determine data association. Examples of data association
functions include, but are not limited to, linear regression,
non-linear mapping/regression, rank (e.g., non-parametric)
correlation, least mean square fit, mean absolute deviation (MAD),
mean absolute relative difference. In one such example, the
correlation coefficient of linear regression is indicative of the
amount of data association of the calibration set that forms the
conversion function, and thus the quality of the calibration.
[0267] The term "quality of calibration" as used herein, is a broad
term and is used in its ordinary sense, including, without
limitation, the statistical association of matched data pairs in
the calibration set used to create the conversion function. For
example, an R-value may be calculated for a calibration set to
determine its statistical data association, wherein an R-value
greater than 0.79 determines a statistically acceptable calibration
quality, while an R-value less than 0.79 determines statistically
unacceptable calibration quality.
[0268] The term "substantially" as used herein, is a broad term and
is used in its ordinary sense, including, without limitation, being
largely but not necessarily wholly that which is specified.
[0269] The term "congruence" as used herein, is a broad term and is
used in its ordinary sense, including, without limitation, the
quality or state of agreeing, coinciding, or being concordant. In
one example, congruence may be determined using rank
correlation.
[0270] The term "concordant" as used herein, is a broad term and is
used in its ordinary sense, including, without limitation, being in
agreement or harmony, and/or free from discord.
[0271] The phrase "continuous (or continual) analyte sensing," as
used herein, is a broad term and is used in its ordinary sense,
including, without limitation, the period in which monitoring of
analyte concentration is continuously, continually, and or
intermittently (but regularly) performed, for example, about every
5 to 10 minutes.
[0272] The term "sensor head," as used herein, is a broad term and
is used in its ordinary sense, including, without limitation, the
region of a monitoring device responsible for the detection of a
particular analyte. In one example, a sensor head comprises a
non-conductive body, a working electrode (anode), a reference
electrode and a counter electrode (cathode) passing through and
secured within the body forming an electrochemically reactive
surface at one location on the body and an electronic connective
means at another location on the body, and a sensing membrane
affixed to the body and covering the electrochemically reactive
surface. The counter electrode has a greater electrochemically
reactive surface area than the working electrode. During general
operation of the sensor a biological sample (e.g. blood or
interstitial fluid) or a portion thereof contacts (directly or
after passage through one or more membranes or domains) an enzyme
(e.g. glucose oxidase); the reaction of the biological sample (or
portion thereof) results in the formation of reaction products that
allow a determination of the analyte (e.g. glucose) level in the
biological sample. In some embodiments, the sensing membrane
further comprises an enzyme domain (e.g., and enzyme layer), and an
electrolyte phase (e.g. a free-flowing liquid phase comprising an
electrolyte-containing fluid described further below).
[0273] The term "electrochemically reactive surface," as used
herein, is a broad term and is used in its ordinary sense,
including, without limitation, the surface of an electrode where an
electrochemical reaction takes place. In the case of the working
electrode, the hydrogen peroxide produced by the enzyme catalyzed
reaction of the analyte being detected creates a measurable
electronic current (e.g. detection of analyte utilizing analyte
oxidase produces H.sub.2O.sub.2 peroxide as a by product,
H.sub.2O.sub.2 reacts with the surface of the working electrode
producing two protons (2H.sup.+), two electrons (2e.sup.-) and one
molecule of oxygen (O.sub.2) which produces the electronic current
being detected). In the case of the counter electrode, a reducible
species, e.g. O.sub.2 is reduced at the electrode surface in order
to balance the current being generated by the working
electrode.
[0274] The term "electronic connection," as used herein, is a broad
term and is used in its ordinary sense, including, without
limitation, any electronic connection known to those in the art
that may be utilized to interface the sensor head electrodes with
the electronic circuitry of a device such as mechanical (e.g. pin
and socket) or soldered.
[0275] The term "sensing membrane," as used herein, is a broad term
and is used in its ordinary sense, including, without limitation, a
permeable or semi-permeable membrane that may be comprised of two
or more domains and constructed of materials of a few microns
thickness or more, which are permeable to oxygen and may or may not
be permeable to an analyte of interest. In one example, the sensing
membrane comprises an immobilized glucose oxidase enzyme, which
enables an electrochemical reaction to occur to measure a
concentration of glucose.
[0276] The term "biointerface membrane," as used herein, is a broad
term and is used in its ordinary sense, including, without
limitation, a permeable membrane that may be comprised of two or
more domains and constructed of materials of a few microns
thickness or more, which may be placed over the sensor body to keep
host cells (e.g. macrophages) from gaining proximity to, and
thereby damaging, the sensing membrane or forming a barrier cell
layer and interfering with the transport of analyte across the
tissue-device interface.
[0277] In the disclosure which follows, the following abbreviations
apply: Eq and Eqs (equivalents); mEq (milliequivalents); M (molar);
mM (millimolar) .mu.M (micromolar); N (Normal); mol (moles); mmol
(millimoles); .mu.mol (micromoles); nmol (nanomoles); g (grams); mg
(milligrams); .mu.g (micrograms); Kg (kilograms); L (liters); mL
(milliliters); dL (deciliters); .mu.L (microliters); cm
(centimeters); mm (millimeters); .mu.m (micrometers); nm
(nanometers); h and hr (hours); min. (minutes); s and sec.
(seconds); .degree. C. (degrees Centigrade).
Overview
[0278] The preferred embodiments relate to the use of an analyte
sensor that measures a concentration of analyte of interest or a
substance indicative of the concentration or presence of the
analyte. In some embodiments, the sensor is a continuous device,
for example a subcutaneous, transdermal, or intravascular device.
In some embodiments, the device may analyze a plurality of
intermittent blood samples. The analyte sensor may use any method
of analyte-sensing, including enzymatic, chemical, physical,
electrochemical, spectrophotometric, polarimetric, calorimetric,
radiometric or the like.
[0279] The analyte sensor uses any known method, including
invasive, minimally invasive, and non-invasive sensing techniques,
to provide an output signal indicative of the concentration of the
analyte of interest. The output signal is typically a raw signal
that is used to provide a useful value of the analyte of interest
to a user, such as a patient or physician, who may be using the
device. Accordingly, appropriate smoothing, calibration, and
evaluation methods may be applied to the raw signal and/or system
as a whole to provide relevant and acceptable estimated analyte
data to the user.
Sensor
[0280] The analyte sensor useful with the preferred embodiments may
be any device capable of measuring the concentration of an analyte
of interest. One exemplary embodiment is described below, which
utilizes an implantable glucose sensor. However, it should be
understood that the devices and methods described herein may be
applied to any device capable of detecting a concentration of
analyte of and providing an output signal that represents the
concentration of the analyte.
[0281] FIG. 1 is an exploded perspective view of a glucose sensor
in one embodiment. The implantable glucose sensor 10 utilizes
amperometric electrochemical sensor technology to measure glucose.
In this exemplary embodiment, a body 12 and a head 14 house
electrodes 16 and sensor electronics, which are described in more
detail with reference to FIG. 2. Three electrodes 16 are operably
connected to the sensor electronics (FIG. 2) and are covered by a
sensing membrane 17 and a biointerface membrane 18, which are
attached by a clip 19. In alternative embodiments, the number of
electrodes may be less than or greater than three.
[0282] The three electrodes 16, which protrude through the head 14,
including a platinum working electrode, a platinum counter
electrode, and a silver/silver chloride reference electrode. The
top ends of the electrodes are in contact with an electrolyte phase
(not shown), which is a free-flowing fluid phase disposed between
the sensing membrane and the electrodes. The sensing membrane 17
includes an enzyme, e.g., glucose oxidase, which covers the
electrolyte phase. In turn, the biointerface membrane 18 covers the
sensing membrane 17 and serves, at least in part, to protect the
sensor from external forces that may result in environmental stress
cracking of the sensing membrane 17.
[0283] In the illustrated embodiment, the counter electrode is
provided to balance the current generated by the species being
measured at the working electrode. In the case of a glucose oxidase
based glucose sensor, the species being measured at the working
electrode is H.sub.2O.sub.2. Glucose oxidase catalyzes the
conversion of oxygen and glucose to hydrogen peroxide and gluconate
according to the following reaction:
Glucose+O.sub.2.fwdarw.Gluconate+H.sub.2O.sub.2
[0284] The change in H.sub.2O.sub.2 can be monitored to determine
glucose concentration because for each glucose molecule
metabolized, there is a proportional change in the product
H.sub.2O.sub.2. Oxidation of H.sub.2O.sub.2 by the working
electrode is balanced by reduction of ambient oxygen, enzyme
generated H.sub.2O.sub.2, or other reducible species at the counter
electrode. The H.sub.2O.sub.2 produced from the glucose oxidase
reaction further reacts at the surface of working electrode and
produces two protons (2H.sup.+), two electrons (2e.sup.-), and one
oxygen molecule (O.sub.2) (See, e.g. Fraser, D. M. "An Introduction
to In vivo Biosensing: Progress and problems." In "Biosensors and
the Body," D. M. Fraser, ed., 1997, pp. 1-56 John Wiley and Sons,
New York.)
[0285] In one embodiment, a potentiostat is used to measure the
electrochemical reaction(s) at the electrode(s) (see FIG. 2). The
potentiostat applies a constant potential between the working and
reference electrodes to produce a current value. The current that
is produced at the working electrode (and flows through the
circuitry to the counter electrode) is proportional to the
diffusional flux of H.sub.2O.sub.2. Accordingly, a raw signal may
be produced that is representative of the concentration of glucose
in the users body, and therefore may be utilized to estimate a
meaningful glucose value, such as described elsewhere herein.
[0286] One problem of enzymatic glucose sensors such as described
above is the non-glucose reaction rate-limiting phenomenon. For
example, if oxygen is deficient, relative to the amount of glucose,
then the enzymatic reaction will be limited by oxygen rather than
glucose. Consequently, the output signal will be indicative of the
oxygen concentration rather than the glucose concentration.
[0287] FIG. 2 is a block diagram that illustrates the sensor
electronics in one embodiment. In this embodiment, the potentiostat
20 is shown, which is operatively connected to electrodes 16 (FIG.
1) to obtain a current value, and includes a resistor (not shown)
that translates the current into voltage. An A/D converter 21
digitizes the analog signal into counts for processing.
Accordingly, the resulting raw data signal in counts is directly
related to the current measured by the potentiostat 20.
[0288] A microprocessor 22 is the central control unit that houses
EEPROM 23 and SRAM 24, and controls the processing of the sensor
electronics. It may be noted that alternative embodiments utilize a
computer system other than a microprocessor to process data as
described herein. In some alternative embodiments, an
application-specific integrated circuit (ASIC) may be used for some
or all the sensor's central processing. The EEPROM 23 provides
semi-permanent storage of data, storing data such as sensor ID and
necessary programming to process data signals (e.g., programming
for data smoothing such as described below). The SRAM 24 is used
for the system's cache memory, for example for temporarily storing
recent sensor data.
[0289] A battery 25 is operatively connected to the microprocessor
22 and provides the necessary power for the sensor. In one
embodiment, the battery is a Lithium Manganese Dioxide battery,
however any appropriately sized and powered battery may be used
(e.g., AAA, Nickel-cadmium, Zinc-carbon, Alkaline, Lithium,
Nickel-metal hydride, Lithium-ion, Zinc-air, Zinc-mercury oxide,
Silver-zinc, or hermetically-sealed). In some embodiments, a
plurality of batteries may be used to power the system. A Quartz
Crystal 26 is operatively connected to the microprocessor 22 and
maintains system time for the computer system as a whole.
[0290] An RF Transceiver 27 is operably connected to the
microprocessor 22 and transmits the sensor data from the sensor to
a receiver (see FIGS. 4 and 5). Although an RF transceiver is shown
here, other embodiments include a wired rather than wireless
connection to the receiver. In yet other embodiments, the receiver
is transcutaneously powered via an inductive coupling, for example.
A quartz crystal 28 provides the system time for synchronizing the
data transmissions from the RF transceiver. It may be noted that
the transceiver 27 may be substituted for a transmitter in one
embodiment.
Data Smoothing
[0291] Typically, an analyte sensor produces a raw data signal that
is indicative of the analyte concentration of a user, such as
described in more detail with reference to FIGS. 1 and 2, above.
However, it is well known that the above described glucose sensor
is only one example of an abundance of analyte sensors that are
able to provide a raw data signal output indicative of the
concentration of the analyte of interest. Thus, it should be
understood that the devices and methods of the preferred
embodiments, including data smoothing, calibration, evaluation, and
other data processing, may be applied to raw data obtained from any
analyte sensor capable of producing a output signal.
[0292] It has been found that raw data signals received from an
analyte sensor include signal noise, which degrades the quality of
the data. Thus, it has been known to use smoothing algorithms help
improve the signal-to-noise ratio in the sensor by reducing signal
jitter, for example. One example of a conventional data smoothing
algorithms include finite impulse response filter (FIR), which is
particularly suited for reducing high-frequency noise (see Steil et
al. U.S. Pat. No. 6,558,351). Other analyte sensors have utilized
heuristic and moving average type algorithms to accomplish data
smoothing of signal jitter in data signals, for example.
[0293] It is advantageous to also reduce signal noise by
attenuating transient, low frequency, non-analyte related signal
fluctuations (e.g., transient ischemia and/or long transient
periods of postural effects that interfere with sensor function due
to lack of oxygen and/or other physiological effects).
[0294] In one embodiment, this attenuation of transient low
frequency non-analyte related signal noise is accomplished using a
recursive filter. In contrast to conventional non-recursive (e.g.,
FIR) filters in which each computation uses new input data sets, a
recursive filter is an equation that uses moving averages as
inputs; that is, a recursive filter includes previous averages as
part of the next filtered output. Recursive filters are
advantageous at least in part due to their computational
efficiency.
[0295] FIG. 3 is a graph that illustrates data smoothing of a raw
data signal in one embodiment. In this embodiment, the recursive
filter is implemented as a digital infinite impulse response filter
(IIR) filter, wherein the output is computed using 6 additions and
7 multiplies as shown in the following equation:
y ( n ) = a 0 * x ( n ) + a 1 * x ( n - 1 ) + a 2 * x ( n - 2 ) + a
3 * x ( n - 3 ) - b 1 * y ( n - 1 ) - b 2 * y ( n - 2 ) - b 3 * y (
n - 3 ) b 0 ##EQU00001##
This polynomial equation includes coefficients that are dependent
on sample rate and frequency behavior of the filter. In this
exemplary embodiment, frequency behavior passes low frequencies up
to cycle lengths of 40 minutes, and is based on a 30 second sample
rate.
[0296] In some embodiments, data smoothing may be implemented in
the sensor and the smoothed data transmitted to a receiver for
additional processing. In other embodiments, raw data may be sent
from the sensor to a receiver for data smoothing and additional
processing therein. In yet other embodiments, the sensor is
integral with the receiver and therefore no transmission of data is
required.
[0297] In one exemplary embodiment, wherein the sensor is an
implantable glucose sensor, data smoothing is performed in the
sensor to ensure a continuous stream of data. In alternative
embodiments, data smoothing may be transmitted from the sensor to
the receiver, and the data smoothing performed at the receiver; it
may be noted however that there may be a risk of transmit-loss in
the radio transmission from the sensor to the receiver when the
transmission is wireless. For example, in embodiments wherein a
sensor is implemented in vivo, the raw sensor signal may be more
consistent within the sensor (in vivo) than the raw signal
transmitted to a source (e.g., receiver) outside the body (e.g., if
a patient were to take the receiver off to shower, communication
between the sensor and receiver may be lost and data smoothing in
the receiver would halt accordingly.) Consequently, it may be noted
that a multiple point data loss in the filter may take, for
example, anywhere from 25 to 40 minutes for the smoothed data to
recover to where it would have been had there been no data
loss.
Receiver
[0298] FIGS. 4A to 4D are schematic views of a receiver in first,
second, third, and fourth embodiments, respectively. A receiver 40
comprises systems necessary to receive, process, and display sensor
data from an analyte sensor, such as described elsewhere herein.
Particularly, the receiver 40 may be a pager-sized device, for
example, and comprise a user interface that has a plurality of
buttons 42 and a liquid crystal display (LCD) screen 44, and which
may include a backlight. In some embodiments the user interface may
also include a keyboard, a speaker, and a vibrator such as
described with reference to FIG. 5.
[0299] FIG. 4A illustrates a first embodiment wherein the receiver
shows a numeric representation of the estimated analyte value on
its user interface, which is described in more detail elsewhere
herein.
[0300] FIG. 4B illustrates a second embodiment wherein the receiver
shows an estimated glucose value and one hour of historical trend
data on its user interface, which is described in more detail
elsewhere herein.
[0301] FIG. 4C illustrates a third embodiment wherein the receiver
shows an estimated glucose value and three hours of historical
trend data on its user interface, which is described in more detail
elsewhere herein.
[0302] FIG. 4D illustrates a fourth embodiment wherein the receiver
shows an estimated glucose value and nine hours of historical trend
data on its user interface, which is described in more detail
elsewhere herein.
[0303] In some embodiments a user is able to toggle through some or
all of the screens shown in FIGS. 4A to 4D using a toggle button on
the receiver. In some embodiments, the user is able to
interactively select the type of output displayed on their user
interface. In some embodiments, the sensor output may have
alternative configurations, such as is described with reference to
FIG. 6, block 69, for example.
[0304] FIG. 5 is a block diagram of the receiver electronics in one
embodiment. It may be noted that the receiver may comprise a
configuration such as described with reference to FIGS. 4A to 4D,
above. Alternatively, the receiver may comprise any configuration,
including a desktop computer, laptop computer, a personal digital
assistant (PDA), a server (local or remote to the receiver), or the
like. In some embodiments, a receiver may be adapted to connect
(via wired or wireless connection) to a desktop computer, laptop
computer, a PDA, a server (local or remote to the receiver), or the
like in order to download data from the receiver. In some
alternative embodiments, the receiver is housed within or directly
connected to the sensor in a manner that allows sensor and receiver
electronics to work directly together and/or share data processing
resources. Accordingly, the receiver, including its electronics,
may be generally described as a "computer system."
[0305] A quartz crystal 50 is operatively connected to an RF
transceiver 51 that together function to receive and synchronize
data signals (e.g., raw data signals transmitted from the RF
transceiver). Once received, the microprocessor 52 processes the
signals, such as described below.
[0306] The microprocessor 52 is the central control unit that
provides the necessary processing, such as calibration algorithms
stored within an EEPROM 53. The EEPROM 53 is operatively connected
to the microprocessor 52 and provides semi-permanent storage of
data, storing data such as receiver ID and necessary programming to
process data signals (e.g., programming for performing calibration
and other algorithms described elsewhere herein). In some
embodiments, an application-specific integrated circuit (ASIC) may
be used for some or all the receiver's central processing. An SRAM
54 is used for the system's cache memory and is helpful in data
processing.
[0307] The microprocessor 52, which is operatively connected to
EEPROM 53 and SRAM 54, controls the processing of the receiver
electronics including, but not limited to, a sensor data receiving
module, a reference data receiving module, a data matching module,
a calibration set module, a conversion function module, a sensor
data transformation module, a quality evaluation module, a
interface control module, and a stability determination module,
which are described in more detail below. It may be noted that any
of the above processing may be programmed into and performed in the
sensor electronics (FIG. 2) in place of, or in complement with, the
receiver electronics (FIG. 5).
[0308] A battery 55 is operatively connected to the microprocessor
52 and provides the necessary power for the receiver. In one
embodiment, the battery is a AAA battery, however any appropriately
sized and powered battery may be used. In some embodiments, a
plurality of batteries may be used to power the system. A quartz
crystal 56 is operatively connected to the microprocessor 52 and
maintains system time for the computer system as a whole.
[0309] A user interface 57 comprises a keyboard, speaker, vibrator,
backlight, LCD, and a plurality of buttons. The components that
comprise the user interface 57 provide the necessary controls to
interact with the user. A keyboard may allow, for example, input of
user information about himself/herself, such as mealtime, exercise,
insulin administration, and reference analyte values. A speaker may
provide, for example, audible signals or alerts for conditions such
as present and/or predicted hyper- and hypoglycemic conditions. A
vibrator may provide, for example, tactile signals or alerts for
reasons such as described with reference to the speaker, above. A
backlight may be provided, for example, to aid the user in reading
the LCD in low light conditions. An LCD may be provided, for
example, to provide the user with visual data output such as
described in more detail with reference to FIGS. 4A to 4D and FIG.
6. Buttons may provide toggle, menu selection, option selection,
mode selection, and reset, for example.
[0310] Communication ports, including a personal computer (PC) corn
port 58 and a reference analyte monitor corn port 59 may be
provided to enable communication with systems that are separate
from, or integral with, the receiver. The PC corn port 58 comprises
means for communicating with another computer system (e.g., PC,
PDA, server, or the like). In one exemplary embodiment, the
receiver is able to download historic data to a physician's PC for
retrospective analysis by the physician. The reference analyte
monitor corn port 59 comprises means for communicating with a
reference analyte monitor so that reference analyte values may be
automatically downloaded into the receiver. In one embodiment, the
reference analyte monitor is integral with the receiver, and the
reference analyte corn port 59 allows internal communication
between the two integral systems. In another embodiment, the
reference analyte monitor corn port 59 allows a wireless or wired
connection to the reference analyte monitor such as a
self-monitoring blood glucose monitor (e.g., for measuring finger
stick blood samples).
Algorithms
[0311] Reference is now made to FIG. 6, which is a flow chart that
illustrates the initial calibration and data output of the sensor
data in one embodiment.
[0312] Calibration of an analyte sensor comprises data processing
that converts sensor data signal into an estimated analyte
measurement that is meaningful to a user. Accordingly, a reference
analyte value is used to calibrate the data signal from the analyte
sensor.
[0313] At block 61, a sensor data receiving module, also referred
to as the sensor data module, receives sensor data (e.g., a data
stream), including one or more time-spaced sensor data points, from
a sensor via the receiver, which may be in wired or wireless
communication with the sensor. The sensor data point(s) may be
smoothed, such as described with reference to FIG. 3, above. It may
be noted that during the initialization of the sensor, prior to
initial calibration, the receiver (e.g., computer system) receives
and stores the sensor data, however may not display any data to the
user until initial calibration and possibly stabilization of the
sensor has been determined.
[0314] At block 62, a reference data receiving module, also
referred to as the reference input module, receives reference data
from a reference analyte monitor, including one or more reference
data points. In one embodiment, the reference analyte points may
comprise results from a self-monitored blood analyte test (e.g.,
from a finger stick test). In one such embodiment, the user may
administer a self-monitored blood analyte test to obtain an analyte
value (e.g., point) using any known analyte sensor, and then enter
the numeric analyte value into the computer system. In another such
embodiment, a self-monitored blood analyte test comprises a wired
or wireless connection to the receiver (e.g. computer system) so
that the user simply initiates a connection between the two
devices, and the reference analyte data is passed or downloaded
between the self-monitored blood analyte test and the receiver. In
yet another such embodiment, the self-monitored analyte test is
integral with the receiver so that the user simply provides a blood
sample to the receiver, and the receiver runs the analyte test to
determine a reference analyte value.
[0315] It may be noted that certain acceptability parameters may be
set for reference values received from the user. For example, in
one embodiment, the receiver may only accept reference analyte
values between about 40 and about 400 mg/dL. Other examples of
determining valid reference analyte values are described in more
detail with reference to FIG. 8.
[0316] At block 63, a data matching module, also referred to as the
processor module, matches reference data (e.g., one or more
reference analyte data points) with substantially time
corresponding sensor data (e.g., one or more sensor data points) to
provide one or more matched data pairs. In one embodiment, one
reference data point is matched to one time corresponding sensor
data point to form a matched data pair. In another embodiment, a
plurality of reference data points are averaged (e.g., equally or
non-equally weighted average, mean-value, median, or the like) and
matched to one time corresponding sensor data point to form a
matched data pair. In another embodiment, one reference data point
is matched to a plurality of time corresponding sensor data points
averaged to form a matched data pair. In yet another embodiment, a
plurality of reference data points are averaged and matched to a
plurality of time corresponding sensor data points averaged to form
a matched data pair.
[0317] In one embodiment, a time corresponding sensor data
comprises one or more sensor data points that occur 15.+-.5 min
after the reference analyte data timestamp (e.g., the time that the
reference analyte data is obtained). In this embodiment, the 15
minute time delay has been chosen to account for an approximately
10 minute delay introduced by the filter used in data smoothing and
an approximately 5 minute physiological time-lag (e.g., the time
necessary for the analyte to diffusion through a membrane(s) of an
analyte sensor). In alternative embodiments, the time corresponding
sensor value may be more or less than the above-described
embodiment, for example .+-.60 minutes. Variability in time
correspondence of sensor and reference data may be attributed to,
for example a longer or shorter time delay introduced by the data
smoothing filter, or if the configuration of the analyte sensor
incurs a greater or lesser physiological time lag.
[0318] It may be noted that in some practical implementations of
the sensor, the reference analyte data may be obtained at a time
that is different from the time that the data is input into the
receiver. Accordingly, it should be noted that the "time stamp" of
the reference analyte (e.g., the time at which the reference
analyte value was obtained) is not the same as the time at which
the reference analyte data was obtained by receiver. Therefore,
some embodiments include a time stamp requirement that ensures that
the receiver stores the accurate time stamp for each reference
analyte value, that is, the time at which the reference value was
actually obtained from the user.
[0319] In some embodiments, tests are used to evaluate the best
matched pair using a reference data point against individual sensor
values over a predetermined time period (e.g., about 30 minutes).
In one such exemplary embodiment, the reference data point is
matched with sensor data points at 5-minute intervals and each
matched pair is evaluated. The matched pair with the best
correlation may be selected as the matched pair for data
processing. In some alternative embodiments, matching a reference
data point with an average of a plurality of sensor data points
over a predetermined time period may be used to form a matched
pair.
[0320] At block 64, a calibration set module, also referred to as
the processor module, forms an initial calibration set from a set
of one or more matched data pairs, which are used to determine the
relationship between the reference analyte data and the sensor
analyte data, such as will be described in more detail with
reference to block 67, below.
[0321] The matched data pairs, which make up the initial
calibration set, may be selected according to predetermined
criteria. It may be noted that the criteria for the initial
calibration set may be the same as, or different from, the criteria
for the update calibration set, which is described in more detail
with reference to FIG. 10. In some embodiments, the number (n) of
data pair(s) selected for the initial calibration set is one. In
other embodiments, n data pairs are selected for the initial
calibration set wherein n is a function of the frequency of the
received reference data points. In one exemplary embodiment, six
data pairs make up the initial calibration set.
[0322] In some embodiments, the data pairs are selected only within
a certain analyte value threshold, for example wherein the
reference analyte value is between about 40 and about 400 mg/dL. In
some embodiments, the data pairs that form the initial calibration
set are selected according to their time stamp. In some
embodiments, the calibration set is selected such as described with
reference to FIG. 10
[0323] At block 65, a stability determination module, also referred
to as the start-up module, determines the stability of the analyte
sensor over a period of time. It may be noted that some analyte
sensors may have an initial instability time period during which
the analyte sensor is unstable for environmental, physiological, or
other reasons. One example of initial sensor instability is an
embodiment wherein the analyte sensor is implanted subcutaneously;
in this example embodiment, stabilization of the analyte sensor may
be dependent upon the maturity of the tissue ingrowth around and
within the sensor. Another example of initial sensor instability is
in an embodiment wherein the analyte sensor is implemented
transdermally; in this example embodiment, stabilization of the
analyte sensor may be dependent upon electrode stabilization and/or
sweat, for example.
[0324] Accordingly, in some embodiments, determination of sensor
stability may include waiting a predetermined time period (e.g., an
implantable sensor is known to require a time period for tissue,
and a transdermal sensor is known to require time to equilibrate
the sensor with the user's skin); in some embodiments, this
predetermined waiting period is between about one minute and about
six weeks. In some embodiments, the sensitivity (e.g., sensor
signal strength with respect to analyte concentration) may be used
to determine the stability of the sensor; for example, amplitude
and/or variability of sensor sensitivity may be evaluated to
determine the stability of the sensor. In alternative embodiments,
detection of pH levels, oxygen, hypochlorite, interfering species
(e.g., ascorbate, urea, and acetaminophen), correlation between
sensor and reference values (e.g., R-value), baseline drift and/or
offset, and the like may be used to determine the stability of the
sensor. In one exemplary embodiment, wherein the sensor is a
glucose sensor, it is known to provide a signal that is associated
with interfering species (e.g., ascorbate, urea, acetaminophen),
which may be used to evaluate sensor stability. In another
exemplary embodiment, wherein the sensor is a glucose sensor such
as described with reference to FIGS. 1 and 2, the counter electrode
can be monitored for oxygen deprivation, which may be used to
evaluate sensor stability or functionality.
[0325] At decision block 66, the system (e.g., microprocessor)
determines whether the analyte sensor is sufficiently stable
according to certain criteria, such as described above. In one
embodiment wherein the sensor is an implantable glucose sensor, the
system waits a predetermined time period believed necessary for
sufficient tissue ingrowth and evaluates the sensor sensitivity
(e.g., between about one minute and six weeks). In another
embodiment, the receiver determines sufficient stability based on
oxygen concentration near the sensor head. In yet another
embodiment, the sensor determines sufficient stability based on a
reassessment of baseline drift and/or offset. In yet another
alternative embodiment, the system evaluates stability by
monitoring the frequency content of the sensor data stream over a
predetermined amount of time (e.g., 24 hours); in this alternative
embodiment, a template (or templates) are provided that reflect
acceptable levels of glucose physiology and are compared with the
actual sensor data, wherein a predetermined amount of agreement
between the template and the actual sensor data is indicative of
sensor stability. It may be noted that a few examples of
determining sufficient stability are given here, however a variety
of known tests and parameters may be used to determine sensor
stability without departing from the spirit and scope of the
preferred embodiments.
[0326] If the receiver does not assess that the stability of the
sensor is sufficient, then the processing returns to block 61,
wherein the receiver receives sensor data such as described in more
detail above. The above-described steps are repeated until
sufficient stability is determined.
[0327] If the receiver does assess that the stability of the sensor
is sufficient, then processing continues to block 67 and the
calibration set is used to calibrate the sensor.
[0328] At block 67, the conversion function module uses the
calibration set to create a conversion function. The conversion
function substantially defines the relationship between the
reference analyte data and the analyte sensor data.
[0329] A variety of known methods may be used with the preferred
embodiments to create the conversion function from the calibration
set. In one embodiment, wherein a plurality of matched data points
form the initial calibration set, a linear least squares regression
is performed on the initial calibration set such as described with
reference to FIG. 7.
[0330] FIG. 7 is a graph that illustrates a regression performed on
a calibration set to create a conversion function in one exemplary
embodiment. In this embodiment, a linear least squares regression
is performed on the initial calibration set. The x-axis represents
reference analyte data; the y-axis represents sensor data. The
graph pictorially illustrates regression of the matched pairs 76 in
the calibration set. Regression calculates a slope 72 and an offset
74 (y=m.times.+b), which defines the conversion function.
[0331] In alternative embodiments other algorithms could be used to
determine the conversion function, for example forms of linear and
non-linear regression, for example fuzzy logic, neural networks,
piece-wise linear regression, polynomial fit, genetic algorithms,
and other pattern recognition and signal estimation techniques.
[0332] In yet other alternative embodiments, the conversion
function may comprise two or more different optimal conversions
because an optimal conversion at any time is dependent on one or
more parameters, such as time of day, calories consumed, exercise,
or analyte concentration above or below a set threshold, for
example. In one such exemplary embodiment, the conversion function
is adapted for the estimated glucose concentration (e.g., high vs.
low). For example in an implantable glucose sensor it has been
observed that the cells surrounding the implant will consume at
least a small amount of glucose as it diffuses toward the glucose
sensor. Assuming the cells consume substantially the same amount of
glucose whether the glucose concentration is low or high, this
phenomenon will have a greater effect on the concentration of
glucose during low blood sugar episodes than the effect on the
concentration of glucose during relatively higher blood sugar
episodes. Accordingly, the conversion function is adapted to
compensate for the sensitivity differences in blood sugar level. In
one implementation, the conversion function comprises two different
regression lines wherein a first regression line is applied when
the estimated blood glucose concentration is at or below a certain
threshold (e.g., 150 mg/dL) and a second regression line is applied
when the estimated blood glucose concentration is at or above a
certain threshold (e.g., 150 mg/dL). In one alternative
implementation, a predetermined pivot of the regression line that
forms the conversion function may be applied when the estimated
blood is above or below a set threshold (e.g., 150 mg/dL), wherein
the pivot and threshold are determined from a retrospective
analysis of the performance of a conversion function and its
performance at a range of glucose concentrations. In another
implementation, the regression line that forms the conversion
function is pivoted about a point in order to comply with clinical
acceptability standards (e.g., Clarke Error Grid, Consensus Grid,
mean absolute relative difference, or other clinical cost
function). Although only a few example implementations are
described, the preferred embodiments contemplate numerous
implementations wherein the conversion function is adaptively
applied based on one or more parameters that may affect the
sensitivity of the sensor data over time.
[0333] Referring again to FIG. 6, at block 68, a sensor data
transformation module uses the conversion function to transform
sensor data into substantially real-time analyte value estimates,
also referred to as calibrated data, as sensor data is continuously
(or intermittently) received from the sensor. For example, in the
embodiment of FIG. 7, the sensor data, which may be provided to the
receiver in "counts", is translated in to estimate analyte value(s)
in mg/dL. In other words, the offset value at any given point in
time may be subtracted from the raw value (e.g., in counts) and
divided by the slope to obtain the estimate analyte value:
mg / dL = ( rawvalue - offset ) slope ##EQU00002##
[0334] In some alternative embodiments, the sensor and/or reference
analyte values are stored in a database for retrospective
analysis.
[0335] At block 69, an output module provides output to the user
via the user interface. The output is representative of the
estimated analyte value, which is determined by converting the
sensor data into a meaningful analyte value such as described in
more detail with reference to block 68, above. User output may be
in the form of a numeric estimated analyte value, an indication of
directional trend of analyte concentration, and/or a graphical
representation of the estimated analyte data over a period of time,
for example. Other representations of the estimated analyte values
are also possible, for example audio and tactile.
[0336] In one exemplary embodiment, such as shown in FIG. 4A, the
estimated analyte value is represented by a numeric value. In other
exemplary embodiments, such as shown in FIGS. 4B to 4D, the user
interface graphically represents the estimated analyte data trend
over predetermined a time period (e.g., one, three, and nine hours,
respectively). In alternative embodiments, other time periods may
be represented.
[0337] In some embodiments, the user interface begins displaying
data to the user after the sensor's stability has been affirmed. In
some alternative embodiments however, the user interface displays
data that is somewhat unstable (e.g., does not have sufficient
stability at block 66); in these embodiments, the receiver may also
include an indication of instability of the sensor data (e.g.,
flashing, faded, or another indication of sensor instability
displayed on the user interface). In some embodiments, the user
interface informs the user of the status of the stability of the
sensor data.
[0338] Accordingly, after initial calibration of the sensor, and
possibly determination of stability of the sensor data, real-time
continuous analyte information may be displayed on the user
interface so that the user may regularly and proactively care for
his/her diabetic condition within the bounds set by his/her
physician.
[0339] In alternative embodiments, the conversion function is used
to predict analyte values at future points in time. These predicted
values may be used to alert the user of upcoming hypoglycemic or
hyperglycemic events. Additionally, predicted values may be used to
compensate for the time lag (e.g., 15 minute time lag such as
described elsewhere herein), so that an estimate analyte value
displayed to the user represents the instant time, rather than a
time delayed estimated value.
[0340] In some embodiments, the substantially real time estimated
analyte value, a predicted future estimate analyte value, a rate of
change, and/or a directional trend of the analyte concentration is
used to control the administration of a constituent to the user,
including an appropriate amount and time, in order to control an
aspect of the user's biological system. One such example is a
closed loop glucose sensor and insulin pump, wherein the analyte
data (e.g., estimated glucose value, rate of change, and/or
directional trend) from the glucose sensor is used to determine the
amount of insulin, and time of administration, that may be given to
a diabetic user to evade hyper- and hypoglycemic conditions.
[0341] Reference is now made to FIG. 8, which is a flow chart that
illustrates the process of evaluating the clinical acceptability of
reference and sensor data in one embodiment. Although some clinical
acceptability tests are disclosed here, any known clinical
standards and methodologies may be applied to evaluate the clinical
acceptability of reference and analyte data herein.
[0342] It may be noted that the conventional analyte meters (e.g.,
self-monitored blood analyte tests) are known to have a +-20% error
in analyte values. For example, gross errors in analyte readings
are known to occur due to patient error in self-administration of
the blood analyte test. In one such example, if the user has traces
of sugar on his/her finger while obtaining a blood sample for a
glucose concentration test, then the measured glucose value will
likely be much higher than the actual glucose value in the blood.
Additionally, it is known that self-monitored analyte tests (e.g.,
test strips) are occasionally subject to manufacturing error.
[0343] Another cause for error includes infrequency and time delay
that may occur if a user does not self-test regularly, or if a user
self-tests regularly but does not enter the reference value at the
appropriate time or with the appropriate time stamp. Therefore, it
may be advantageous to validate the acceptability of reference
analyte values prior to accepting them as valid entries.
Accordingly, the receiver evaluates the clinical acceptability of
received reference analyte data prior to their acceptance as a
valid reference value.
[0344] In one embodiment, the reference analyte data (and/or sensor
analyte data) is evaluated with respect to substantially time
corresponding sensor data (and/or substantially time corresponding
reference analyte data) to determine the clinical acceptability of
the reference analyte and/or sensor analyte data. Clinical
acceptability considers a deviation between time corresponding
glucose measurements (e.g., data from a glucose sensor and data
from a reference glucose monitor) and the risk (e.g., to the
decision making of a diabetic patient) associated with that
deviation based on the glucose value indicated by the sensor and/or
reference data. Evaluating the clinical acceptability of reference
and sensor analyte data, and controlling the user interface
dependent thereon, may minimize clinical risk.
[0345] In one embodiment, the receiver evaluates clinical
acceptability each time reference data is obtained. In another
embodiment, the receiver evaluates clinical acceptability after the
initial calibration and stabilization of the sensor, such as
described with reference to FIG. 6, above. In some embodiments, the
receiver evaluates clinical acceptability as an initial pre-screen
of reference analyte data, for example after determining if the
reference glucose measurement is between about 40 and 400 mg/dL. In
other embodiments, other methods of pre-screening data may be used,
for example by determining if a reference analyte data value is
physiologically feasible based on previous reference analyte data
values (e.g., below a maximum rate of change).
[0346] After initial calibration such as described in more detail
with reference to FIG. 6, the sensor data receiving module 61
receives substantially continuous sensor data (e.g., a data stream)
via a receiver and converts that data into estimated analyte
values. As used herein, "substantially continuous" is broad enough
to include a data stream of individual measurements taken at time
intervals (e.g., time-spaced) ranging from fractions of a second up
to, e.g., 1, 2, or 5 minutes. As sensor data is continuously
converted, it may be occasionally recalibrated such as described in
more detail with reference FIG. 10. Initial calibration and
re-calibration of the sensor requires a reference analyte value.
Accordingly, the receiver may receive reference analyte data at any
time for appropriate processing. These reference analyte values may
be evaluated for clinical acceptability such as described below as
a fail-safe against reference analyte test errors.
[0347] At block 81, the reference data receiving module, also
referred to as the reference input module, receives reference
analyte data from a reference analyte monitor. In one embodiment,
the reference data comprises one analyte value obtained from a
reference monitor. In some alternative embodiments however, the
reference data includes a set of analyte values entered by a user
into the interface and averaged by known methods such as described
elsewhere herein.
[0348] In some embodiments, the reference data is pre-screened
according to environmental and physiological issues, such as time
of day, oxygen concentration, postural effects, and patient-entered
environmental data. In one example embodiment, wherein the sensor
comprises an implantable glucose sensor, an oxygen sensor within
the glucose sensor is used to determine if sufficient oxygen is
being provided to successfully complete the necessary enzyme and
electrochemical reactions for glucose sensing. In another example
embodiment wherein the sensor comprises an implantable glucose
sensor, the counter electrode could be monitored for a
"rail-effect", that is, when insufficient oxygen is provided at the
counter electrode causing the counter electrode to reach
operational (e.g., circuitry) limits. In yet another example
embodiment, the patient is prompted to enter data into the user
interface, such as meal times and/or amount of exercise, which
could be used to determine likelihood of acceptable reference
data.
[0349] It may be further noted that evaluation data, such as
described in the paragraph above, may be used to evaluate an
optimum time for reference analyte measurement. Correspondingly,
the user interface may then prompt the user to provide a reference
data point for calibration within a given time period.
Consequently, because the receiver proactively prompts the user
during optimum calibration times, the likelihood of error due to
environmental and physiological limitations may decrease and
consistency and acceptability of the calibration may increase.
[0350] At block 82, the clinical acceptability evaluation module,
also referred to as clinical module, evaluates the clinical
acceptability of newly received reference data and/or time
corresponding sensor data. In some embodiments of evaluating
clinical acceptability, the rate of change of the reference data as
compared to previous data is assessed for clinical acceptability.
That is, the rate of change and acceleration (or deceleration) of
many analytes has certain physiological limits within the body.
Accordingly, a limit may be set to determine if the new matched
pair is within a physiologically feasible range, indicated by a
rate of change from the previous data that is within known
physiological and/or statistical limits. Similarly, in some
embodiments any algorithm that predicts a future value of an
analyte may be used to predict and then compare an actual value to
a time corresponding predicted value to determine if the actual
value falls within a clinically acceptable range based on the
predictive algorithm, for example.
[0351] In one exemplary embodiment, the clinical acceptability
evaluation module 82 matches the reference data with a
substantially time corresponding converted sensor value such as
described with reference to FIG. 6 above, and plots the matched
data on a Clarke Error Grid such as described in more detail with
reference to FIG. 9.
[0352] FIG. 9 is a graph of two data pairs on a Clarke Error Grid
to illustrate the evaluation of clinical acceptability in one
exemplary embodiment. The Clarke Error Grid may be used by the
clinical acceptability evaluation module to evaluate the clinical
acceptability of the disparity between a reference glucose value
and a sensor glucose (e.g., estimated glucose) value, if any, in an
embodiment wherein the sensor is a glucose sensor. The x-axis
represents glucose reference glucose data and the y-axis represents
estimated glucose sensor data. Matched data pairs are plotted
accordingly to their reference and sensor values, respectively. In
this embodiment, matched pairs that fall within the A and B regions
of the Clarke Error Grid are considered clinically acceptable,
while matched pairs that fall within the C, D, and E regions of the
Clarke Error Grid are not considered clinically acceptable.
Particularly, FIG. 9 shows a first matched pair 92 is shown which
falls within the A region of the Clarke Error Grid, therefore is it
considered clinically acceptable. A second matched pair 94 is shown
which falls within the C region of the Clarke Error Grid, therefore
it is not considered clinically acceptable.
[0353] It may be noted that a variety of other known methods of
evaluation of clinical acceptability may be utilized. In one
alternative embodiment, the Consensus Grid is used to evaluate the
clinical acceptability of reference and sensor data. In another
alternative embodiment, a mean absolute difference calculation may
be used to evaluate the clinical acceptability of the reference
data. In another alternative embodiment, the clinical acceptability
may be evaluated using any relevant clinical acceptability test,
such as a known grid (e.g., Clarke Error or Consensus), and
including additional parameters such as time of day and/or the
increase or decreasing trend of the analyte concentration. In
another alternative embodiment, a rate of change calculation may be
used to evaluate clinical acceptability. In yet another alternative
embodiment, wherein the received reference data is in substantially
real time, the conversion function could be used to predict an
estimated glucose value at a time corresponding to the time stamp
of the reference analyte value (this may be required due to a time
lag of the sensor data such as described elsewhere herein).
Accordingly, a threshold may be set for the predicted estimated
glucose value and the reference analyte value disparity, if
any.
[0354] Referring again to FIG. 8, the results of the clinical
acceptability evaluation are assessed. If clinical acceptability is
determined with the received reference data, then processing
continues to block 84 to optionally recalculate the conversion
function using the received reference data in the calibration set.
If, however, clinical acceptability is not determined, then the
processing progresses to block 86 to control the user interface,
such as will be described with reference to block 86 below.
[0355] At block 84, the conversion function module optionally
recreates the conversion function using the received reference
data. In one embodiment, the conversion function module adds the
newly received reference data (e.g., including the matched sensor
data) into the calibration set, displaces the oldest, and/or least
concordant matched data pair from the calibration set, and
recalculates the conversion function accordingly. In another
embodiment, the conversion function module evaluates the
calibration set for best calibration based on inclusion criteria,
such as described in more detail with reference to FIG. 10.
[0356] At 85, the sensor data transformation module uses the
conversion function to continually (or intermittently) convert
sensor data into estimated analyte values, also referred to as
calibrated data, such as described in more detail with reference to
FIG. 6, block 68.
[0357] At block 86, the interface control module, also referred to
as the fail-safe module, controls the user interface based upon the
clinical acceptability of the reference data received. If the
evaluation (block 82) deems clinical acceptability, then the user
interface may function as normal; that is, providing output for the
user such as described in more detail with reference to FIG. 6,
block 69.
[0358] If however the reference data is not considered clinically
acceptable, then the fail-safe module begins the initial stages of
fail-safe mode. In some embodiments, the initial stages of
fail-safe mode include altering the user interface so that
estimated sensor data is not displayed to the user. In some
embodiments, the initial stages of fail-safe mode include prompting
the user to repeat the reference analyte test and provide another
reference analyte value. The repeated analyte value is then
evaluated for clinical acceptability such as described with
reference to blocks 81 to 83, above.
[0359] If the results of the repeated analyte test are determined
to be clinically unacceptable, then fail-safe module may alter the
user interface to reflect full fail-safe mode. In one embodiment,
full fail-safe mode includes discontinuing sensor analyte display
output on the user interface. In other embodiments, color-coded
information, trend information, directional information (e.g.,
arrows or angled lines), gauges, and/or fail-safe information may
be displayed, for example.
[0360] If the results of the repeated analyte test are determined
to be clinically acceptable, then the first analyte value is
discarded, and the repeated analyte value is accepted. The process
returns to block 84 to optionally recalculate the conversion
function, such as described in more detail with reference to block
84, above.
[0361] Reference is now made to FIG. 10, which is a flow chart that
illustrates the process of evaluation of calibration data for best
calibration based on inclusion criteria of matched data pairs in
one embodiment.
[0362] It may be noted that calibration of analyte sensors may be
variable over time; that is, the conversion function suitable for
one point in time may not be suitable for another point in time
(e.g., hours, days, weeks, or months later). For example, in an
embodiment wherein the analyte sensor is subcutaneously
implantable, the maturation of tissue ingrowth over time may cause
variability in the calibration of the analyte sensor. As another
example, physiological changes in the user (e.g., metabolism,
interfering blood constituents, lifestyle changes) may cause
variability in the calibration of the sensor. Accordingly, a
continuously updating calibration algorithm is disclosed that
includes reforming the calibration set, and thus recalculating the
conversion function, over time according to a set of inclusion
criteria.
[0363] At block 101, the reference data receiving module, also
referred to as the reference input module, receives a new reference
analyte value (e.g., data point) from the reference analyte
monitor. In some embodiments, the reference analyte value may be
pre-screened according to criteria such as described in more detail
with reference to FIG. 6, block 62. In some embodiments, the
reference analyte value may be evaluated for clinical acceptability
such as described in more detail with reference to FIG. 8.
[0364] At block 102, the data matching module, also referred to as
the processor module, forms one or more updated matched data pairs
by matching new reference data to substantially time corresponding
sensor data, such as described in more detail with reference to
FIG. 6, block 63.
[0365] At block 103, a calibration evaluation module evaluates the
new matched pair(s) inclusion into the calibration set. In some
embodiments, the receiver simply adds the updated matched data pair
into the calibration set, displaces the oldest and/or least
concordant matched pair from the calibration set, and proceeds to
recalculate the conversion function accordingly (block 105).
[0366] In some embodiments, the calibration evaluation includes
evaluating only the new matched data pair. In some embodiments, the
calibration evaluation includes evaluating all of the matched data
pairs in the existing calibration set and including the new matched
data pair; in such embodiments not only is the new matched data
pair evaluated for inclusion (or exclusion), but additionally each
of the data pairs in the calibration set are individually evaluated
for inclusion (or exclusion). In some alternative embodiments, the
calibration evaluation includes evaluating all possible
combinations of matched data pairs from the existing calibration
set and including the new matched data pair to determine which
combination best meets the inclusion criteria. In some additional
alternative embodiments, the calibration evaluation includes a
combination of at least two of the above-described embodiments.
[0367] Inclusion criteria comprise one or more criteria that define
a set of matched data pairs that form a substantially optimal
calibration set. One inclusion criterion comprises ensuring the
time stamp of the matched data pairs (that make up the calibration
set) span at least a set time period (e.g., three hours). Another
inclusion criterion comprises ensuring that the time stamps of the
matched data pairs are not more than a set age (e.g., one week
old). Another inclusion criterion ensures that the matched pairs of
the calibration set have a substantially distributed amount of high
and low raw sensor data, estimated sensor analyte values, and/or
reference analyte values. Another criterion comprises ensuring all
raw sensor data, estimated sensor analyte values, and/or reference
analyte values are within a predetermined range (e.g., 40 to 400
mg/dL for glucose values). Another criterion comprises evaluating
the rate of change of the analyte concentration (e.g., from sensor
data) during the time stamp of the matched pair(s). For example,
sensor and reference data obtained during the time when the analyte
concentration is undergoing a slow rate of change may be less
susceptible inaccuracies caused by time lag and other physiological
and non-physiological effects. Another criterion comprises
evaluating the congruence of respective sensor and reference data
in each matched data pair; the matched pairs with the most
congruence may be chosen. Another criterion comprises evaluating
physiological changes (e.g., low oxygen due to a user's posture
that may effect the function of a subcutaneously implantable
analyte sensor, or other effects such as described with reference
to FIG. 6) to ascertain a likelihood of error in the sensor value.
It may be noted that evaluation of calibration set criteria may
comprise evaluating one, some, or all of the above described
inclusion criteria. It is contemplated that additional embodiments
may comprise additional inclusion criteria not explicitly described
herein.
[0368] At block 104, the evaluation of the calibration set
determines whether to maintain the previously established
calibration set, or if the calibration set should be updated (e.g.,
modified) with the new matched data pair. In some embodiments, the
oldest matched data pair is simply displaced when a new matched
data pair is included. It may be noted however that a new
calibration set may include not only the determination to include
the new matched data pair, but in some embodiments, may also
determine which of the previously matched data pairs should be
displaced from the calibration set.
[0369] At block 105, the conversion function module recreates the
conversion function using the modified calibration set. The
calculation of the conversion function is described in more detail
with reference to FIG. 6.
[0370] At block 106, the sensor data transformation module converts
sensor data to calibrated data using the updated conversion
function. Conversion of raw sensor data into estimated analyte
values is described in more detail with reference to FIG. 6.
[0371] Reference is now made to FIG. 11, which is a flow chart that
illustrates the process of evaluating the quality of the
calibration in one embodiment. The calibration quality may be
evaluated by determining the statistical association of data that
forms the calibration set, which determines the confidence
associated with the conversion function used in calibration and
conversion of raw sensor data into estimated analyte values.
[0372] In one embodiment calibration quality may be evaluated after
initial or updated calculation of the conversion function such as
described elsewhere herein. However it may be noted that
calibration quality may be performed at any time during the data
processing.
[0373] At block 111, a sensor data receiving module, also referred
to as the sensor data module, receives the sensor data from the
sensor such as described in more detail with reference to FIG.
6.
[0374] At block 112, a reference data receiving module, also
referred to as the reference input module, receives reference data
from a reference analyte monitor, such as described in more detail
with reference to FIG. 6.
[0375] At block 113, the data matching module, also referred to as
the processor module, matches received reference data with
substantially time corresponding sensor data to provide one or more
matched data pairs, such as described in more detail with reference
to FIG. 6.
[0376] At block 114, the calibration set module, also referred to
as the processor module, forms a calibration set from one or more
matched data pairs such as described in more detail with reference
to FIGS. 6, 8, and 10.
[0377] At block 115, the conversion function module calculates a
conversion function using the calibration set, such as described in
more detail with reference to FIGS. 6, 8, and 10.
[0378] At block 116, the sensor data transformation module
continuously (or intermittently) converts received sensor data into
estimated analyte values, also referred to as calibrated data, such
as described in more detail with reference to FIGS. 6, 8, and
10.
[0379] At block 117, a quality evaluation module evaluates the
quality of the calibration. In one embodiment, the quality of the
calibration is based on the association of the calibration set data
using statistical analysis. Statistical analysis may comprise any
known cost function such as linear regression, non-linear
mapping/regression, rank (e.g., non-parametric) correlation, least
mean square fit, mean absolute deviation (MAD), mean absolute
relative difference, and the like. The result of the statistical
analysis provides a measure of the association of data used in
calibrating the system. A threshold of data association may be set
to determine if sufficient quality is exhibited in a calibration
set.
[0380] In another embodiment, the quality of the calibration is
determined by evaluating the calibration set for clinical
acceptability, such as described with reference to blocks 82 and 83
(e.g., Clarke Error Grid, Consensus Grid, or clinical acceptability
test). As an example, the matched data pairs that form the
calibration set may be plotted on a Clarke Error Grid, such that
when all matched data pairs fall within the A and B regions of the
Clarke Error Grid, then the calibration is determined to be
clinically acceptable.
[0381] In yet another alternative embodiment, the quality of the
calibration is determined based initially on the association of the
calibration set data using statistical analysis, and then by
evaluating the calibration set for clinical acceptability. If the
calibration set fails the statistical and/or the clinical test, the
processing returns to block 115 to recalculate the conversion
function with a new (e.g., optimized) set of matched data pairs. In
this embodiment, the processing loop (block 115 to block 117)
iterates until the quality evaluation module 1) determines clinical
acceptability, 2) determines sufficient statistical data
association, 3) determines both clinical acceptability and
sufficient statistical data association, or 4) surpasses a
threshold of iterations; after which the processing continues to
block 118.
[0382] FIGS. 12A and 12B illustrate one exemplary embodiment
wherein the accuracy of the conversion function is determined by
evaluating the correlation coefficient from linear regression of
the calibration set that formed the conversion function. In this
exemplary embodiment, a threshold (e.g., 0.79) is set for the
R-value obtained from the correlation coefficient.
[0383] FIGS. 12A and 12B are graphs that illustrate an evaluation
of the quality of calibration based on data association in one
exemplary embodiment using a correlation coefficient. Particularly,
FIGS. 12A and 12B pictorially illustrate the results of the linear
least squares regression performed on a first and a second
calibration set (FIGS. 12A and 12B, respectively). The x-axis
represents reference analyte data; the y-axis represents sensor
data. The graph pictorially illustrates regression that determines
the conversion function.
[0384] It may be noted that the regression line (and thus the
conversion function) formed by the regression of the first
calibration set of FIG. 12A is the same as the regression line (and
thus the conversion function) formed by the regression of the
second calibration set of FIG. 12B. However, the correlation of the
data in the calibration set to the regression line in FIG. 12A is
significantly different than the correlation of the data in the
calibration set to the regression line in FIG. 12A. In other words,
there is a noticeably greater deviation of the data from the
regression line in FIG. 12B than the deviation of the data from the
regression line in FIG. 12A.
[0385] In order to quantify this difference in correlation, an
R-value may be used to summarize the residuals (e.g., root mean
square deviations) of the data when fitted to a straight line via
least squares method, in this exemplary embodiment. R-value may be
calculated according to the following equation:
R = i ( x i - x _ ) ( y i - y _ ) i ( x i - x ) 2 i y i - y ) 2
##EQU00003##
In the above equation: i is an index (1 to n), x is a reference
analyte value, y is a sensor analyte value, x is an average of 1/n
reference analyte values, and y is an average of 1/n sensor analyte
values.
[0386] In the exemplary calibration set shown in FIG. 12A, the
calculated R-value is about 0.99, which may also be expressed as
the correlation coefficient of regression. Accordingly, the
calibration exhibits sufficient data association (and thus
insufficient quality) because it falls above the 0.79 threshold set
in this exemplary embodiment.
[0387] In the exemplary calibration set shown in FIG. 12B, the
calculated R-value is about 0.77, which may also be expressed as
the correlation coefficient of regression. Accordingly, the
calibration exhibits insufficient data association (and thus
insufficient quality) because it falls below the 0.79 threshold set
in this exemplary embodiment.
[0388] Reference is again made to FIG. 11, at block 118, the
interface control module, also referred to as the fail-safe module,
controls the user interface based upon the quality of the
calibration. If the calibration is exhibits sufficient quality,
then the user interface may function as normal; that is providing
output for the user such as described in more detail with reference
to FIG. 6.
[0389] If however the calibration is not deemed sufficient in
quality, then fail-safe module 118 begins the initial stages of
fail-safe mode, which are described in more detail with reference
to FIG. 8. In some embodiments, the initial stages of fail-safe
mode include altering the user interface so that estimated sensor
data is not displayed to the user. In some embodiments, the initial
stages of fail-safe mode also include prompting the user to provide
an updated reference analyte value. The updated analyte value is
then processed as described above and the updated conversion
function that results from the repeated reference analyte test, if
any, is evaluated for statistical accuracy.
[0390] If the results of the updated evaluation again exhibit
insufficient quality, then the fail-safe module alters user
interface to reflect full fail-safe mode, which is described in
more detail with reference to FIG. 8. If however the results of the
updated evaluation exhibit sufficient quality, then the first
reference analyte value is discarded, and the repeated reference
analyte value is accepted and the process continues as described
herein.
[0391] It may be noted that the initial stages of fail-safe mode
and full fail safe mode may be similar to that described with
reference to FIG. 8, including user interface control for example.
Additionally, it is contemplated herein that a variety of
difference modes between initial and full fail-safe mode may be
provided depending on the relative quality of the calibration. In
other words, the confidence level of the calibration quality may
control a plurality of different user interface screens providing
error bars, .+-.values, and the like. Similar screens may be
implements in the clinical acceptability embodiments described with
reference to FIG. 8.
[0392] The above description discloses several methods and
materials of the disclosed invention. This invention is susceptible
to modifications in the methods and materials, as well as
alterations in the fabrication methods and equipment. Such
modifications will become apparent to those skilled in the art from
a consideration of this disclosure or practice of the invention
disclosed herein. Consequently, it is not intended that this
invention be limited to the specific embodiments disclosed herein,
but that it cover all modifications and alternatives coming within
the true scope and spirit of the invention as embodied in the
attached claims. All patents, applications, and other references
cited herein are hereby incorporated by reference in their
entirety.
* * * * *