U.S. patent application number 11/121207 was filed with the patent office on 2005-09-08 for method and apparatus for using alternative site glucose determinations to calibrate and maintain noninvasive and implantable analyzers.
Invention is credited to Blank, Thomas B., Hazen, Kevin H., Henderson, James R., Monfre, Stephen L., Ruchti, Timothy L..
Application Number | 20050196821 11/121207 |
Document ID | / |
Family ID | 27808636 |
Filed Date | 2005-09-08 |
United States Patent
Application |
20050196821 |
Kind Code |
A1 |
Monfre, Stephen L. ; et
al. |
September 8, 2005 |
Method and apparatus for using alternative site glucose
determinations to calibrate and maintain noninvasive and
implantable analyzers
Abstract
A method and apparatus for calibrating noninvasive or
implantable glucose analyzers uses either alternative invasive
glucose determinations or noninvasive glucose determinations for
calibrating noninvasive or implantable glucose analyzers. Use of an
alternative invasive or noninvasive glucose determination in the
calibration allows minimization of errors due to sampling
methodology, and spatial and temporal variations that are built
into the calibration model. An additional embodiment uses
statistical correlations between noninvasive and alternative
invasive glucose determinations and traditional invasive glucose
determinations to adjust noninvasive or alternative invasive
glucose concentrations to traditional invasive glucose
concentrations. The invention provides a means for calibrating on
the basis of glucose determinations that reflect the matrix
observed and the variable measured by the analyzer more closely. A
glucose analyzer couples an invasive fingerstick meter to a
noninvasive glucose analyzer for calibration, validation,
adaptation, and safety check of the calibration model embodied in
the noninvasive analyzer.
Inventors: |
Monfre, Stephen L.;
(Gilbert, AZ) ; Hazen, Kevin H.; (Gilbert, AZ)
; Ruchti, Timothy L.; (Gilbert, AZ) ; Blank,
Thomas B.; (Chandler, AZ) ; Henderson, James R.;
(Phoenix, AZ) |
Correspondence
Address: |
GLENN PATENT GROUP
3475 EDISON WAY, SUITE L
MENLO PARK
CA
94025
US
|
Family ID: |
27808636 |
Appl. No.: |
11/121207 |
Filed: |
May 2, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11121207 |
May 2, 2005 |
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10377916 |
Feb 28, 2003 |
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60362899 |
Mar 8, 2002 |
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60362885 |
Mar 8, 2002 |
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Current U.S.
Class: |
435/14 |
Current CPC
Class: |
A61B 5/1455 20130101;
G01N 21/274 20130101; A61B 5/14532 20130101; G01N 21/49 20130101;
G01N 21/359 20130101; A61B 5/1495 20130101 |
Class at
Publication: |
435/014 |
International
Class: |
C12Q 001/54 |
Claims
1. A method for accounting for sampling-related differences in
blood glucose measurements, comprising the steps of: providing a
transform that models a relationship between sets of glucose
measurements, wherein each set comprises samples collected in a
different manner; and converting subsequent measurements according
to said transform.
2. The method of claim 1, wherein said sets of glucose measurements
comprise either of a set of alternate invasive measurements and a
set of traditional invasive measurements, or a set of noninvasive
and a set of traditional invasive measurements.
3. The method of claim 2, wherein said relationship comprises any
of: a magnitude difference; a lag; a phase difference; and a width
difference.
4. The method of claim 3, wherein said transform embodies an
algorithm, said algorithm comprising the step of: dividing a set of
measurements by said magnitude difference.
5. The method of claim 3, wherein said transform embodies an
algorithm, said algorithm comprising the step of: subtracting said
lag from a set of measurements.
6. The method of claim 3, wherein said transform embodies an
algorithm, said algorithm comprising the step of: subtracting said
phase difference from a set of measurements.
7. The method of claim 3, wherein said transform embodies an
algorithm, said algorithm comprising the step of: adjusting a set
of alternative invasive glucose concentrations with said width
difference.
8. The method of claim 2, wherein said sets of measurements are
generated during periodic testing after a carbohydrate load.
9. The method of claim 2, wherein subsequent measurements comprise
any of: single measurements; and sets of measurements.
10. The method of claim 1, wherein said step of converting
subsequent measurements comprises the step of: converting between
traditional invasive measurements and alternative invasive
measurements.
11. The method of claim 1, wherein said step of converting
subsequent measurements comprises the step of: converting between
noninvasive measurements predicted from a calibration based on
alternative invasive measurements, and traditional invasive
measurements.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This Application is a divisional application of U.S. patent
application Ser. No. 10/377,916, filed Feb. 28, 2003, which claims
benefit of U.S. provisional patent application Ser. No. 60/362,899,
filed Mar. 8, 2002 and U.S. provisional patent application Ser. No.
60/362,885, filed Mar. 8, 2002, each of which is incorporated
herein in its entirety by this reference thereto.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates generally to the calibration and
maintenance of glucose analyzers. More particularly, the invention
relates to the use of alternative site glucose determinations to
improve algorithm development, calibration, and/or quality control
of noninvasive or implantable glucose analyzers.
[0004] 2. Background Information
[0005] Diabetes is a chronic disease that results in improper
production and utilization of insulin, a hormone that facilitates
glucose uptake into cells. While a precise cause of diabetes is
unknown, genetic factors, environmental factors, and obesity appear
to play roles. Diabetics have increased risk in three broad
categories: cardiovascular heart disease, retinopathy, and
neuropathy. Diabetics may have one or more of the following
complications: heart disease and stroke, high blood pressure,
kidney disease, neuropathy (nerve disease and amputations),
retinopathy, diabetic ketoacidosis, skin conditions, gum disease,
impotence, and fetal complications. Diabetes is a leading cause of
death and disability worldwide. Moreover, diabetes is merely one
among a group of disorders of glucose metabolism that also includes
impaired glucose tolerance, and hyperinsulinemia, or
hypoglycemia.
[0006] Diabetes Prevalence and Trends
[0007] Diabetes is an ever more common disease. The World Health
Organization (WHO) estimates that diabetes currently afflicts 154
million people worldwide. There are 54 million people with diabetes
living in developed countries. The WHO estimates that the number of
people with diabetes will grow to 300 million by the year 2025. In
the United States, 15.7 million people or 5.9 per cent of the
population are estimated to have diabetes. Within the United
States, the prevalence of adults diagnosed with diabetes increased
by six percent in 1999 and rose by 33 percent between 1990 and
1998. This corresponds to approximately eight hundred thousand new
cases every year in America. The estimated total cost to the United
States economy alone exceeds $90 billion per year. Diabetes
Statistics, National Institutes of Health, Publication No. 98-3926,
Bethesda, Md. (November 1997).
[0008] Long-term clinical studies show that the onset of
complications can be significantly reduced through proper control
of blood glucose levels. The Diabetes Control and Complications
Trial Research Group, The effect of intensive treatment of diabetes
on the development and progression of long-term complications in
insulin-dependent diabetes mellitus, N Eng J of Med, 329:977-86
(1993); U.K. Prospective Diabetes Study (UKPDS) Group, Intensive
blood-glucose control with sulphonylureas or insulin compared with
conventional treatment and risk of complications in patients with
type 2 diabetes, Lancet, 352:837-853 (1998); and Y. Ohkubo, H.
Kishikawa, E. Araki, T. Miyata, S. Isami, S. Motoyoshi, Y. Kojima,
N. Furuyoshi, M. Shichizi, Intensive insulin therapy prevents the
progression of diabetic microvascular complications in Japanese
patients with non-insulin-dependent diabetes mellitus: a randomized
prospective 6-year study, Diabetes Res Clin Pract, 28:103-117
(1995).
[0009] A vital element of diabetes management is the
self-monitoring of blood glucose levels by diabetics in the home
environment. However, current monitoring techniques discourage
regular use due to the inconvenient and painful nature of drawing
blood through the skin prior to analysis. The Diabetes Control and
Complication Trial Research Group, supra. As a result, noninvasive
measurement of glucose has been identified as a beneficial
development for the management of diabetes. Implantable glucose
analyzers eventually coupled to an insulin delivery system
providing an artificial pancreas are also being pursued.
[0010] Glucose Measurement History, Approaches, and
Technologies
[0011] Diabetes treatment has progressed through several stages.
The combined development of insulin therapy and in-home glucose
determination led to a radical improvement in the lives of
diabetics. Home glucose determination has also progressed through
its own succession of stages. Urine tests for glucose have given
way to the invasive fingerstick glucose determinations that are
more accurate but somewhat painful, also presenting a possible
biohazard. The development of alternative site glucose
determinations has somewhat mitigated the pain aspects, but may
have introduced a new difficulty as a result of temporal and
spatial differences in glucose between the well perfused fingertip
and the less well perfused alternative sites. Additionally, the
biohazard issue remains. Current research is focusing on the
development of noninvasive technologies that will totally eliminate
the pain associated with glucose determination and fluid biohazard
issues. Finally, considerable progress has been made in implantable
or full-loop systems incorporating both glucose determination and
insulin delivery that will result in the realization of an
artificial pancreas. Blood glucose determination may currently be
categorized into four major types:
[0012] traditional invasive;
[0013] alternative invasive;
[0014] noninvasive; and
[0015] implantable.
[0016] Due to the wide use of these modes of measurement and
somewhat loose utilization of terminology in the literature, a
detailed summary of the terminology for each mode of measurement is
provided here in order to clarify usage of the terms herein.
[0017] In the medical field, the term `invasive` is customarily
applied to surgical methods and procedures, generally involving at
least some trauma or injury to the tissue, such as cutting, in
order to achieve their object. However, in the glucose
determination field, the term `invasive` is defined relative to
noninvasive. `Noninvasive` clearly describes methods, invariably
signal-based, in which no biological sample or fluid is taken from
the body in order to perform a glucose measurement. `Invasive` then
means that a biological sample is collected from the body. Invasive
glucose determinations may then be further broken into two separate
groups. The first is a `traditional invasive` method in which a
blood sample is collected from the body from an artery, vein, or
capillary bed in the fingertips or toes. The second is an
`alternative invasive` method in which a sample of blood,
interstitial fluid, or biological fluid is drawn from a region
other than an artery, vein, or capillary bed in the fingertips or
toes.
[0018] 1. Traditional Invasive Glucose Determination
[0019] There are three major categories of traditional (classic)
invasive glucose determinations. The first two utilize blood drawn
with a needle from an artery or vein, respectively. The third
consists of capillary blood obtained via lancet from the fingertip
or toes. Over the past two decades, this has become the most common
method for self-monitoring of blood glucose.
[0020] Common technologies are utilized to analyze the blood
collected by venous or arterial draw and finger stick approaches.
Glucose analysis includes techniques such as colorimetric and
enzymatic glucose analysis. The most common enzymatic based glucose
analyzers utilize glucose oxidase, which catalyzes the reaction of
glucose with oxygen to form gluconolactone and hydrogen peroxide as
shown by equation 1, infra. Glucose determination includes
techniques based upon depletion of oxygen in the sample either
through the changes in sample pH, or through the formation of
hydrogen peroxide. A number of colorimetric and electro-enzymatic
techniques further utilize the reaction products as a starting
reagent. For example, hydrogen peroxide reacts in the presence of
platinum to form the hydrogen ion, oxygen, and current; any of
which may be utilized indirectly to determine the glucose
concentration, as in equation 2.
glucose+O.sub.2.fwdarw.gluconolactone+H.sub.2O.sub.2 (1)
H.sub.2O.sub.2.fwdarw.2H.sup.++O.sub.2+2e.sup.- (2)
[0021] It is noted that a number of alternative site methodologies
such as the THERASENSE FREESTYLE (THERASENSE, INC., Alameda Calif.)
collect blood samples from regions other than the fingertip or
toes. These technologies are not herein referred to as traditional
invasive glucose meters unless the sample is drawn from the
fingertip or toes despite having similar chemical analyses such as
the colorimetric or enzymatic analysis described above. However,
the same device utilized to collect blood via lancet from sample
sites consisting of the fingertip or toe is a traditional invasive
glucose analyzer.
[0022] 2. Alternative Invasive Glucose Determination
[0023] There are several alternative invasive methods of
determining glucose concentration. A first group of alternative
invasive glucose analyzers have a number of similarities to the
traditional invasive glucose analyzers. One similarity is that
blood samples are acquired with a lancet. Obviously, this form of
alternative invasive glucose determination while unsuitable for
analysis of venous or arterial blood, may be utilized to collect
capillary blood samples. A second similarity is that the blood
sample is analyzed using chemical analyses that resemble the
colorimetric and enzymatic analyses describe above. The primary
difference, however, is that in an alternative invasive glucose
determination the blood sample is not collected from the fingertip
or toes. For example, according to package labeling, the THERASENSE
FREESTYLE meter may be utilized to collect and analyze blood from
the forearm. This is an alternative invasive glucose determination
due to the location of the lancet draw. In this first group of
alternative invasive methods based upon blood draws with a lancet,
a primary difference between the alternative invasive and
traditional invasive glucose determination is the location of the
site of blood acquisition from the body. Additional differences
include factors such as the gauge of the lancet, the depth of
penetration of the lancet, timing issues, the volume of blood
acquired, and environmental factors such as the partial pressure of
oxygen, altitude, and temperature. This form of alternative
invasive glucose determination includes samples collected from the
palmar region, base of thumb, forearm, upper arm, head, earlobe,
torso, abdominal region, thigh, calf, and plantar region.
[0024] A second group of alternative invasive glucose analyzers is
distinguished by their mode of sample acquisition. This group of
glucose analyzers has a common characteristic of acquiring a
biological sample from the body or modifying the surface of the
skin to gather a sample without utilization of a lancet for
subsequent analysis. For example, a laser poration based glucose
analyzer utilizes a burst or stream of photons to create a small
hole in the skin surface. A sample of substantially interstitial
fluid collects in the resulting hole. Subsequent analysis of the
sample for glucose constitutes an alternative invasive glucose
analysis, whether or not the sample was actually removed from the
created hole. A second common characteristic is that a device and
algorithm are utilized to determine glucose from the sample.
Herein, the term alternative invasive includes techniques that
analyze biosamples such as interstitial fluid, whole blood,
mixtures of interstitial fluid and whole blood, and selectively
sampled interstitial fluid. An example of selectively sampled
interstitial fluid is collected fluid in which large or less mobile
constituents are not fully represented in the resulting sample. For
this second group of alternative invasive glucose analyzers
sampling sites include: the hand, fingertips, palmar region, base
of thumb, forearm, upper arm, head, earlobe, eye, chest, torso,
abdominal region, thigh, calf, foot, plantar region, and toes. A
number of methodologies exist for the collection of samples for
alternative invasive measurements including:
[0025] Laser poration: In these systems, photons of one or more
wavelengths are applied to skin creating a small hole in the skin
barrier. This allows small volumes of interstitial fluid to become
available for a number of sampling techniques;
[0026] Applied current: In these systems, a small electrical
current is applied to the skin allowing interstitial fluid to
permeate through the skin;
[0027] Suction: In these systems, a partial vacuum is applied to a
local area on the surface of the skin. Interstitial fluid permeates
the skin and is collected.
[0028] In all of the above techniques, the analyzed sample is
interstitial fluid. However, some of these same techniques can be
applied to the skin in a fashion that draws blood. For example, the
laser poration method can result in blood droplets. As described
herein, any technique that draws biosamples from the skin without
the use of a lancet on the fingertip or toes is referred to as an
alternative invasive technique. In addition, it is recognized that
the alternative invasive systems each use different sampling
approaches that lead to different subsets of the interstitial fluid
being collected. For example, large proteins might lag behind in
the skin while smaller, more diffusive, elements may be
preferentially sampled. This leads to samples being collected with
varying analyte and interferent concentrations. Another example is
that a mixture of whole blood and interstitial fluid may be
collected. These techniques may be utilized in combination. For
example the SOFT-TACT, also known as the SOFTSENSE (ABBOT
LABORATORIES, INC, Abbot Park Ill.), applies suction to the skin
followed by a lancet stick. Despite the differences in sampling,
these techniques are referred to as alternative invasive techniques
sampling interstitial fluid.
[0029] The literature occasionally refers to the alternative
invasive technique as an alternative site glucose determination or
as a minimally invasive technique. The minimally invasive
nomenclature derives from the method by which the sample is
collected. As described herein, the alternative site glucose
determinations that draw blood or interstitial fluid, even %
microliter, are considered to be alternative invasive glucose
determination techniques as defined above. Examples of alternative
invasive techniques include the THERASENSE FREESTYLE when not
sampling fingertips or toes, the GLUCOWATCH (CYGNUS, INC., Redwood
City Calif.) the ONE TOUCH ULTRA (LIFESCAN, INC., Milpitas Calif.),
and equivalent technologies.
[0030] A wide range of technologies serve to analyze biosamples
collected with alternative invasive techniques. The most common of
these technologies are:
[0031] Conventional: With some modification, the interstitial fluid
samples may be analyzed by most of the technologies utilized to
determine glucose concentrations in serum, plasma, or whole blood.
These include electrochemical, electroenzymatic, and colorimetric
approaches. For example, the enzymatic and colorimetric approaches
described above may also be used to determine the glucose
concentration in interstitial fluid samples;
[0032] Spectrophotometric: A number of approaches for determining
the glucose concentration in biosamples, have been developed that
utilize spectrophotometric technologies. These techniques include:
Raman and fluorescence, as well as techniques using light from the
ultraviolet through the infrared [ultraviolet (200 to 400 nm),
visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000
cm.sup.-1), and infrared (2500 to 14,285 nm or 4000 to 700
cm.sup.-1)].
[0033] As used herein, the term invasive glucose analyzer
encompasses both traditional invasive glucose analyzers and
alternative invasive glucose analyzers.
[0034] 3. Noninvasive Glucose Determination
[0035] There exist a number of noninvasive approaches for glucose
determination. These approaches vary widely, but have at least two
common steps. First, an apparatus is utilized to acquire a signal
from the body without obtaining a biological sample. Second, an
algorithm is utilized to convert this signal into a glucose
determination.
[0036] One type of noninvasive glucose determination is based upon
spectra. Typically, a noninvasive apparatus utilizes some form of
spectroscopy to acquire the signal or spectrum from the body.
Utilized spectroscopic techniques include, but are not limited to:
Raman and fluorescence, as well as techniques using light from
ultraviolet through the infrared [ultraviolet (200 to 400 nm),
visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000
cm.sup.-1), and infrared (2500 to 14,285 nm or 4000 to 700
cm.sup.-1)]. A particular range for noninvasive glucose
determination in diffuse reflectance mode is about 1100 to 2500 nm
or ranges therein. K. Hazen, Glucose Determination in Biological
Matrices Using Near-Infrared Spectroscopy, doctoral dissertation,
University of Iowa (1995). It is important to note that these
techniques are distinct from the traditional invasive and
alternative invasive techniques listed above in that the sample
interrogated is a portion of the human body in-situ, not a
biological sample acquired from the human body.
[0037] Typically, three modes are utilized to collect noninvasive
scans: transmittance, transflectance, and/or diffuse reflectance.
For example the signal collected, typically consisting of light or
a spectrum, may be transmitting through a region of the body such
as a fingertip, diffusely reflected, or transflected. Transflected
here refers to collection of the signal not at the incident point
or area (diffuse reflectance), and not at the opposite side of the
sample (transmittance), but rather at some point on the body
between the transmitted and diffuse reflectance collection area.
For example, transflected light enters the fingertip or forearm in
one region and exits in another region typically 0.2 to 5 mm or
more away depending on the wavelength utilized. Thus, light that is
strongly absorbed by the body such as light near water absorbance
maxima at 1450 or 1950 nm would need to be collected after a small
radial divergence and light that is less absorbed such as light
near water absorbance minima at 1300, 1600, or 2250 nm may be
collected at greater radial or transflected distances from the
incident photons.
[0038] Noninvasive techniques are not limited to using the
fingertip as a measurement site. Alternative sites for taking
noninvasive measurements include: a hand, finger, palmar region,
base of thumb, forearm, volar aspect of the forearm, dorsal aspect
of the forearm, upper arm, head, earlobe, eye, tongue, chest,
torso, abdominal region, thigh, calf, foot, plantar region, and
toe. It is important to note that noninvasive techniques do not
have to be based upon spectroscopy. For example, a bioimpedence
meter would be considered a noninvasive device. Within the context
of the invention, any device that reads a signal from the body
without penetrating the skin and collecting a biological sample is
referred to as a noninvasive glucose analyzer. For example, a
bioimpedence meter is a noninvasive device.
[0039] An alternative reference method is a reference determination
made at a location on the body not including the fingertips and
toes. An alternative reference includes both an alternative
invasive measurement and an alternative site noninvasive
measurement. Hence, an alternative site noninvasive measurement is
a noninvasive measurement made at physiological sites excluding the
fingertips and toes.
[0040] 4. Implantable Sensor for Glucose Determination
[0041] There exist a number of approaches for implanting a glucose
sensor into the body for glucose determination. These implantables
may be utilized to collect a sample for further analysis or may
acquire a reading or signal from the sample directly or indirectly.
Two categories of implantable glucose analyzers exist: short-term
and long-term.
[0042] As referred to herein, a device or a collection apparatus is
at least a short-term implantable (as opposed to a long-term
implantable) if part of the device penetrates the skin for a period
of greater than 3 hours and less than one month. For example, a
wick placed subcutaneously to collect a sample overnight that is
removed and analyzed for glucose content representative of the
interstitial fluid glucose concentration is referred to as a short
term implantable. Similarly, a biosensor or electrode placed under
the skin for a period of greater than three hours that reads a
signal indicative of a glucose concentration or level, directly or
indirectly is referred to as at least a short-term implantable
device. Conversely, devices described above based upon techniques
like a lancet, applied current, laser poration, or suction are
referred to as either a traditional invasive or alternative
invasive technique as they do not fulfill both the three hour and
skin penetration parameters. As described herein, long-term
implantables are distinguished from short-term implantables by
having the criteria that they must both penetrate the skin and be
utilized for a period of one month or longer. Long term
implantables may remain in the body for many years.
[0043] Implantable glucose analyzers vary widely, but have at least
several features in common. First, at least part of the device
penetrates the skin. More commonly, the entire device is imbedded
into the body. Second, the apparatus is utilized to acquire either
a sample of the body or a signal relating directly or indirectly to
the glucose concentration within the body. If the implantable
device collects a sample, readings or measurements on the sample
may be collected after removal from the body. Alternatively,
readings or signals may be transmitted from within the body by the
device or utilized for such purposes as insulin delivery while in
the body. Third, an algorithm is utilized to convert the signals
into readings directly or indirectly related to the glucose
concentration. An implantable analyzer may read signals from one or
more of a variety of body fluids or tissues including but not
limited to: arterial blood, venous blood, capillary blood,
interstitial fluid, and selectively sampled interstitial fluid. An
implantable analyzer may also collect glucose information from skin
tissue, cerebral spinal fluid, organ tissue, or through an artery
or vein. For example, an implantable glucose analyzer may be placed
transcutaneously, in the peritoneal cavity, in an artery, in
muscle, or in an organ such as the liver or brain. The implantable
glucose sensor may be one component of an artificial pancreas.
[0044] Examples of implantable glucose monitors follow. One example
of a CGMS (continuous glucose monitoring system) is a group of
glucose monitors based upon open-flow microperfusion. Z.
Trajanowski, G. Brunner, L. Schaupp, M. Ellmerer, P. Wach, T.
Pieber, P. Kotanko, F. Skrabai, Open-flow microperfusion of
subcutaneous adipose tissue for on-line continuous ex vivo
measurement of glucose concentration, Diabetes Care, 20:1114-1120
(1997). Another example utilizes implanted sensors that comprise
biosensors and amperometric sensors. Z. Trajanowski, P. Wach, R.
Gfrerer, Portable device for continuous fractionated blood sampling
and continuous ex vivo blood glucose monitoring, Biosensors and
Bioelectronics, 11:479-487 (1996). Another example is the MINIMED
CGMS (MEDTRONIC, INC., Minneapolis Minn.).
Description of Related Technology
[0045] Glucose Concentration Measured at Fingertip vs. Alternative
Sampling Locations
[0046] Many authors claim that alternative site glucose
concentrations are equivalent to fingerstick glucose determination.
A number of examples are summarized below:
[0047] Szuts, et al. conclude that measurable physiological
differences in glucose concentration between the arm and fingertip
could be determined, but that these differences were found to be
clinically insignificant even in those subjects in whom they were
measured. E. Szuts, J. Lock, K. Malomo, A. Anagnostopoulos, Althea,
Blood glucose concentrations of arm and finger during dynamic
glucose conditions, Diabetes Technology & Therapeutics, 4:3-11
(2002).
[0048] Lee, et al. concluded that patients testing two hours
postprandial could expect to see small differences between their
forearm and fingertip glucose concentrations. D. Lee, S. Weinert,
E. Miller, A study of forearm versus finger stick glucose
monitoring, Diabetes Technology & Therapeutics, 4:13-23
(2002).
[0049] Bennion, et al. concluded that there is no significant
difference in HbA.sub.1C measurements for patients utilizing
alternative site meters off of the fingertip and traditional
glucose analyzers on the fingertip. N. Bennion, N. Christensen, G.
McGarraugh, Alternate site glucose testing: a crossover design,
Diabetes Technology & Therapeutics, 4:25-33 (2002). This is an
indirect indication that the forearm and fingertip glucose
concentrations are the same, though many additional factors such as
pain and frequency of testing will impact the study.
[0050] Peled, et al. concluded that glucose monitoring of blood
samples from the forearm is suitable when expecting steady state
glycemic conditions and that the palm samples produced a close
correlation with fingertip glucose determinations under all
glycemic states. N. Peled, D. Wong, S. Gwalani, Comparison of
glucose levels in capillary blood samples from a variety of body
sites, Diabetes Technology & Therapeutics, 4:35-44 (2002).
[0051] Based upon a study utilizing fast acting insulin injected
intravenously, Jungheim, et al. suggested that to avoid risky
delays in hyperglycemia and hypoglycemia detection, monitoring at
the arm should be limited to situations in which ongoing rapid
changes in the blood glucose concentration can be excluded. K.
Jungheim, T. Koschinsky, Glucose monitoring at the arm, Diabetes
Care, 25:956-960 (2002); and K. Jungheim; T. Koschinsky, Risky
delay of hypoglycemia detection by glucose monitoring at the arm,
Diabetes Care, 24:1303-1304 (2001). The use of intravenous insulin
in this study was criticized as creating physiological extremes
that influence the observed differences. G. McGarraugh, Response to
Jungheim and Koschinsky, Diabetes Care, 24:1304:1306 (2001).
[0052] Equilibration Approaches
[0053] While there exist multiple reports that glucose
concentrations are very similar when collected from the fingertip
or alternative locations, a number of sampling approaches have been
recommended to increase localized perfusion at the sample site to
equilibrate the values just prior to sampling. Several of these
approaches are summarized below:
[0054] Pressure: One sampling methodology requires rubbing or
applying pressure to the sampling site in order to increase
localized perfusion prior to obtaining a sample via lancet. An
example of this is the FREESTYLE blood glucose analyzer
(THERASENSE, INC., supra). G. McGarraugh, S. Schwartz, R.
Weinstein, Glucose Measurements Using Blood Extracted from the
Forearm and the Finger, THERASENSE, INC., ART01022 Rev. C (2001);
and G. McGarraugh, D. Price, S. Schwartz, R. Weinstein,
Physiological influences on off-finger glucose testing, Diabetes
Technology & Therapeutics, 3:367-376 (2001).
[0055] Heating: Heat applied to the localized sample site has been
proposed as a mechanism for equalizing the concentration between
the vascular system and skin tissue. This may be to dilate the
capillaries allowing more blood flow, which leads towards
equalization of the venous and capillary glucose concentrations.
Alternatively, vasodilating agents such as nicotinic acid, methyl
nicotinamide, minoxidil, nitroglycerin, histamine, capsaicin, or
menthol can be utilized to increase local blood flow. M.
Rohrscheib, C. Gardner, M. Robinson, Method and apparatus for
noninvasive blood analyte measurement with fluid compartment
equilibration, U.S. Pat. No. 6,240,306 (May 29, 2001).
[0056] Vacuum: Applying a partial vacuum to the skin at and around
the sampling site prior to sample collection has also been
utilized. A localized deformation in the skin may allow superficial
capillaries to fill more completely. T. Ryan, A study of the
epidermal capillary unit in psoriasis, Dermatologica, 138:459-472
(1969). For example, ABBOT LABORATORIES, INC. utilizes a vacuum
device at one-half atmosphere that pulls the skin up 3.5 mm into
their device. ABBOT maintains this deformation results in increased
perfusion that equalizes the glucose concentration between the
alternative site and the fingertip. R. Ng, Presentation to the FDA
at the Clinical Chemistry & Clinical Toxicology Devices Panel
Meeting, Gaithersburg Md. (Oct. 29, 2001).
[0057] Calibration:
[0058] Glucose analyzers require calibration. This is true for all
types of glucose analyzers such as traditional invasive,
alternative invasive, noninvasive, and implantable analyzers. One
fact associated with noninvasive glucose analyzers is the fact that
they are secondary in nature, that is, they do not measure blood
glucose levels directly. This means that a primary method is
required to calibrate these devices to measure blood glucose levels
properly. Many methods of calibration exist.
[0059] Calibration of Traditional Invasive Glucose Analyzers:
[0060] Glucose meters or analyzers may be calibrated off of
biological samples such as whole blood, serum, plasmas, or modified
solutions of these samples. In addition, glucose analyzers may be
calibrated with a range of whole blood samples, modified whole
blood samples, blood simulants, phantoms, or a range of chemically
prepared standards. Typically, these samples have glucose
concentrations that span the desired functionality range of the
glucose analyzer. For glucose analyzers, this is approximately 70
to 400 mg/dL. Some go further into the hypoglycemic range, down to
40 or even 0 mg/dL, while some go well into the hyperglycemic
range, up to 700 or 1000 mg/dL.
[0061] Calibration of Alternative Invasive Glucose Analyzers:
[0062] Alternative invasive glucose analyzers utilize many of the
invasive glucose calibration procedures. When calibrating the
alternative invasive glucose meters that utilize biological fluids
such as blood or interstitial fluid as a reference, relatively
minor modifications to the traditional calibration approaches may
be required.
[0063] Calibration of Noninvasive Glucose Analyzers:
[0064] One noninvasive technology, near-infrared spectroscopy,
provides the opportunity for both frequent and painless noninvasive
measurement of glucose. This approach involves the illumination of
a spot on the body with near-infrared (NIR) electromagnetic
radiation, light in the wavelength range 700 to 2500 nm. The light
is partially absorbed and scattered, according to its interaction
with the constituents of the tissue. The actual tissue volume that
is sampled is the portion of irradiated tissue from which light is
transflected or diffusely transmitted to the spectrometer detection
system. With near-infrared spectroscopy, a mathematical
relationship between an in vivo near-infrared measurement and the
actual blood glucose value needs to be developed. This is achieved
through the collection of in vivo NIR measurements with
corresponding blood glucose values that have been obtained directly
through the use of measurement tools like the HEMOCUE (YSI
INCORPORATED, Yellow Springs Ohio), or any appropriate and accurate
traditional invasive reference device.
[0065] For spectrophotometric based analyzers, there are several
univariate and multivariate methods that can be used to develop the
mathematical relationship between the measured signal and the
actual blood glucose value. However, the basic equation being
solved is known as the Beer-Lambert Law. This law states that the
strength of an absorbance/reflectance measurement is proportional
to the concentration of the analyte which is being measured, as in
equation 3,
A=.epsilon.bC (3)
[0066] where A is the absorbance/reflectance measurement at a given
wavelength of light, .epsilon. is the molar absorptivity associated
with the molecule of interest at the same given wavelength, b is
the distance that the light travels, and C is the concentration of
the molecule of interest (glucose).
[0067] Chemometric calibration techniques extract the glucose
signal from the measured spectrum through various methods of signal
processing and calibration including one or more mathematical
models. The models are still developed through the process of
calibration on the basis of an exemplary set of spectral
measurements known as the calibration set and associated set of
reference blood glucose values based upon an analysis of fingertip
capillary blood or venous blood. Common multivariate approaches
requiring an exemplary reference glucose concentration vector for
each sample spectrum in a calibration include partial least squares
(PLS) and principal component regression (PCR). Many additional
forms of calibration are known, such as neural networks.
[0068] Because every method has error, it is desirable that the
primary device used to measure blood glucose be as accurate as
possible to minimize the error that propagates through the
mathematical relationship developed. While it appears reasonable to
assume that any FDA-approved blood glucose monitor should be
suitable, for accurate verification of the secondary method, a
monitor having a percentage error of less than 5 percent is
desirable. Meters with increased percentage error such as 10
percent may also be acceptable, though the error of the device
being calibrated may increase.
[0069] Although the above is well-understood, one aspect that is
forgotten is that secondary methods require constant verification
that they are providing consistent and accurate measurements when
compared to the primary method. This means that a method for
checking blood glucose values directly and comparing those values
with the given secondary method is required. Such monitoring is
manifested in quality assurance and quality control programs. Bias
adjustments are often made to a calibration. In some cases the most
appropriate calibration is selected based upon these secondary
methods. S. Malin, T. Ruchti, Intelligent system for noninvasive
blood analyte prediction, U.S. Pat. No. 6,280,381 (Aug. 28, 2001).
This approach is also known as validation.
[0070] The Problem:
[0071] Calibration of a noninvasive glucose analyzer entails some
complications not observed in traditional invasive glucose
analyzers. For example, spectroscopic or spectrophotometric based
noninvasive glucose analyzers probe a sample that is not entirely
whole blood or interstitial fluid. Photons penetrate into the body,
interact with body layers and/or tissues and are detected upon
reemerging from the body. Hence, many possible interferences exist
that do not exist in a prepared reference or calibration sample. In
addition, the interferences and matrices encountered are part of a
living being and hence are dynamic in nature. For these reasons,
indirect calibration is often attempted with traditional invasive
reference glucose determinations collected from the fingertip. This
approach, however, introduces errors into the noninvasive analyzer
that are associated with sampling the reference glucose
concentration. One key source of error is the difference between
glucose concentrations at the site tested by the noninvasive
glucose analyzer and the reference site sampled with an invasive
technology. Thus, it would be an important advance in the art to
provide methods for calibrating and maintaining signal-based
analyzers that addressed the negative effect on their accuracy and
precision that results from calibrating them based on invasive
reference samples taken at sites distant from the site of
noninvasive sampling.
SUMMARY OF THE INVENTION
[0072] The invention provides a method and apparatus for using
either alternative invasive glucose determinations or alternative
site noninvasive glucose determinations for calibrating noninvasive
or implantable glucose analyzers. Use of an alternative invasive or
alternative site noninvasive glucose determination in the
calibration allows for minimization of errors built into the
glucose analyzer model, including errors due to sampling,
methodology, and errors due to temporal and spatial variations of
glucose concentration within the subject's body. In addition, the
invention provides conversion of glucose concentrations determined
from noninvasive or alternative reference determinations into
traditional invasive glucose determinations. As described herein,
the use of an alternative invasive or noninvasive glucose
determination for calibration is also understood to include their
use for glucose determination, prediction, calibration transfer,
calibration maintenance, quality control, and quality
assurance.
[0073] The use of alternative invasive or alternative site
noninvasive reference determinations provides a means for
calibrating on the basis of glucose determinations that reflect the
matrix observed and the variable measured by the analyzer more
closely. Statistical correlations between noninvasive and
alternative invasive glucose determinations and traditional
invasive glucose determinations may then be used to adjust
alternative site noninvasive or alternative invasive glucose
concentrations to traditional invasive glucose concentrations. The
invention also provides an apparatus in which an invasive stick
meter is coupled to a noninvasive glucose analyzer for calibration,
validation, adaptation, and safety check of the calibration model
embodied in the noninvasive analyzer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0074] FIG. 1 provides a plot of glucose measurements that
demonstrates large differences in glucose concentration between the
fingertip and forearm according to the invention;
[0075] FIG. 2 provides a plot of glucose measurements that
demonstrates a lag in glucose concentrations determined from the
forearm compared to the fingertip according to the invention;
[0076] FIG. 3 shows a plot of fingertip and forearm glucose
concentrations that are well correlated;
[0077] FIG. 4 illustrates a plot that demonstrates historesis in
glucose concentration profiles resulting in differences in glucose
concentration between the fingertip and forearm even when glucose
concentrations are at a local minimum with respect to time
according to the invention;
[0078] FIG. 5 provides a plot of forearm glucose concentrations
against corresponding fingertip glucose concentrations with a
relatively large error according to the invention;
[0079] FIG. 6 provides a plot of forearm glucose concentrations
against corresponding contralateral forearm glucose concentrations
with a smaller error when compared to FIG. 5, according to the
invention;
[0080] FIG. 7 shows a block diagram of a noninvasive analyzer using
alternative site glucose determinations calibration and maintenance
according to the invention;
[0081] FIG. 8 shows a plot of predicted glucose concentrations
versus reference forearm glucose determinations according to the
invention;
[0082] FIG. 9 provides a plot of predicted glucose concentration
versus traditional invasive reference glucose concentrations;
[0083] FIG. 10 provides a histogram demonstrating a statistical
difference in the histogram shift of predicted glucose
concentrations versus fingertip and forearm reference
concentrations according to the invention;
[0084] FIG. 11 provides a histogram demonstrating a statistical
difference in the histogram magnitude of predicted glucose
concentrations versus fingertip and forearm reference
concentrations according to the invention;
[0085] FIG. 12 provides a plot of subjects demonstrating dampened
and lagged glucose predictions versus traditional invasive
reference glucose concentrations according to the invention;
[0086] FIG. 13 illustrates a concentration correlation plot of the
series of subjects with dampened and lagged glucose predictions
versus traditional invasive reference glucose concentrations
according to the invention;
[0087] FIG. 14 shows a plot of lag and magnitude adjusted glucose
predictions overlaid with traditional invasive glucose
determinations according to the invention;
[0088] FIG. 15 provides a concentration correlation plot of the lag
and magnitude adjusted glucose predictions versus traditional
invasive reference glucose concentrations according to the
invention;
[0089] FIG. 16 shows an algorithm-adjusted concentration
correlation plot of predicted glucose concentration versus
traditional reference glucose concentrations according to the
invention; and
[0090] FIG. 17 shows a block diagram of an apparatus including a
noninvasive glucose analyzer coupled with an invasive (traditional
or alternative) glucose monitor according to the invention.
DETAILED DESCRIPTION
[0091] The present invention reduces the error in the reference
glucose concentration for the calibration of glucose sensors and
therefore leads to a more accurate, precise, and robust glucose
measurement system.
[0092] Difference in Traditional Invasive and Alternative Invasive
Glucose Concentration
[0093] Initially, differences between traditional invasive and
alternative invasive glucose determinations are demonstrated. It is
demonstrated here that the differences between the alternative
invasive glucose concentration from a site such as the forearm and
the glucose concentration from a traditional invasive fingerstick
vary as a function of at least time and location. Additional
parameters include sampling methodology, physiology, and glucose
analyzer instrumentation.
EXAMPLE #1
[0094] In a first example, variation of glucose concentration at
locations in the body is demonstrated at fixed points in time. A
total of twenty diabetic subjects were run through one of two
glucose profiles each having two peaks so that the resulting curves
formed the shape of an `M,` shown in part in FIG. 1, over a period
of eight hours. Thus, glucose concentration started low at around
80 mg/dL, was increased to approximately 350 mg/dL, and was brought
back to about 80 mg/dL in a period of about four hours. The cycle
was immediately repeated to form an `M`-shaped glucose
concentration profile. These profiles were alternately generated
with intake of a liquid form of carbohydrate (50-100 g) or intake
of a solid form of carbohydrate (50-100 g) in combination with
insulin to generate the two excursions of the `M` profile.
Traditional invasive fingertip capillary glucose concentrations
were determined every 15 minutes throughout the 8-hour period. Each
fingertip determination was immediately followed by an alternative
invasive capillary glucose determinations wherein samples were
collected from the volar aspect of the subject's right and then
left forearms. The resulting data set included 1920 data points (20
subjects*3 sites/15 minutes*32 draws/day). J. Fischer, K. Hazen, M.
Welch, L. Hockersmith, J. Coates, Comparisons of capillary blood
glucose concentrations from the fingertips and the volar aspects of
the left and right forearms, American Diabetes Association,
62.sup.nd Annual Meeting, (Jun. 14, 2002). The `M`-shaped profiles
described above may be induced according to procedures previously
set forth in L. Hockersmith, A method of producing a glycemic
profile of predetermined shape in a test subject, U.S. patent
application Ser. No. 09/766,427 (Jan. 18, 2001), the entirety of
which is hereby incorporated by reference as if fully set forth
herein.
[0095] Four partial `M` profiles from the above study are presented
here. In FIG. 1, alternative invasive glucose concentrations
measured at the forearm are demonstrated to have both a dampened
and a lagged profile versus the traditional invasive fingertip
glucose concentrations. For this individual, when the glucose
concentration was rising the forearm glucose concentrations are
observed to be substantially dampened, that is lower than the
corresponding fingertip glucose concentration. For example, at the
90 minute mark the fingertip glucose concentration of 234 mg/dL is
more than 100 mg/dL higher than either the left or right forearm
glucose concentration of 123 and 114 mg/dL, respectively. In
addition, the peak glucose concentration observed at the fingertip
of 295 mg/dL is both larger and occurred 30 minutes earlier than
the peak forearm glucose concentration of 259 mg/dL. Finally, the
forearm glucose concentrations have a small lag versus the
fingertip glucose concentrations. FIG. 2 presents another glucose
profile in which many of the same effects just described are
observed but to a lesser degree. For example, the rising glucose
concentrations of the alternative invasive forearm glucose
concentrations are still less than those of the traditional
invasive fingertip glucose concentrations, but the difference is
smaller. A dampening and lag of the alternative invasive peak are
still observed. One measure of dampening is the range of
traditional invasive glucose concentrations minus the range of
alternative invasive glucose concentrations. In addition, the lag
is more pronounced than in the previous figure. FIG. 3 demonstrates
another example in which the forearm glucose concentrations closely
track those of the fingertip glucose concentrations. Finally, FIG.
4 demonstrates a historesis effect as a subject moves through
subsequent glucose excursions. That is, a lag observed in a forearm
may still be observed at a later time. In this case, dampening of
the forearm glucose concentration is observed at a glucose minimum
relative to that of the fingertip glucose concentration. The
effects observed above are representative as a whole of the glucose
profiles observed in the study outlined above.
[0096] As in FIG. 5, alternative invasive glucose determinations
collected from the volar aspect of each subject's left and right
forearm are plotted against the time-associated traditional
invasive fingertip reference glucose concentration for all subjects
in a concentration correlation plot overlaid with a Clarke error
grid. The standard error of the forearm glucose concentrations
versus the fingertip glucose concentration is relatively large at
37.7 mg/dL with an F-value of 4.43. The best fit of the data yields
a slope of 0.76 and an intercept of 41.4 mg/dL. This is consistent
with dampened and delayed forearm glucose profiles relative to the
fingertip and results in only 73.8% of the points falling in the
`A` region of the Clarke error grid.
[0097] The glucose determinations collected from the volar aspect
of each subject's left and right forearm are plotted against each
other for all subjects on a Clarke error grid in FIG. 6. The
standard error of the left forearm glucose concentrations versus
the right forearm glucose concentration is reduced to 17.2 mg/dL
with an F-value of 16.0. The best fit of the data yields a slope of
0.96 and an intercept of 8.3 mg/dL. This is consistent with a
reduction in the dampening and delay of left forearm glucose
profiles relative to the right forearm glucose concentrations and
results in 95.8 percent of the points falling in the `A` region of
the Clarke error grid. A slope of 0.96, combined with the low
standard error, indicates that the capillary blood glucose values
of the left and right volar forearm would be similar.
[0098] These data suggest several conclusions:
[0099] during a glucose excursion, substantial differences are
often observed between the capillary blood glucose of the untreated
forearm and the fingertip;
[0100] fast changes in blood glucose concentration magnify
differences between the measured blood glucose concentration of the
fingertip and forearm while the relative errors are proportional to
the glucose concentration;
[0101] during periods of rapid change in blood glucose
concentration, differences between the forearm and fingertip give
rise to a higher percentage of points in less desirable regions of
the Clarke error grid;
[0102] the measured blood glucose concentrations of the volar
aspect of the left and right forearms appear similar; and
[0103] finally, these findings are consistent with the phenomenon
of decreased perfusion into the forearm versus that of the
fingertip, leading to a dampening and/or lag in the glucose
profile.
[0104] These conclusions are consistent with those reported in the
circulatory physiology literature and that relating to sampling
approaches of alternative invasive glucose analyzers. It has been
reported that blood flow in the fingers is 33.+-.10 mL/g/min at
20.degree. C. while in the leg, forearm, and abdomen the blood flow
is 4-6 mL/g/min at 19-22.degree. C. V. Harvey, Sparks, skin and
muscle, in: Peripheral Circulation, P. Johnson, ed., p. 198, New
York (1978). This is consistent with the observed differences in
localized blood glucose concentration. When glucose concentrations
vary rapidly a difference develops throughout the body in local
blood glucose concentrations as a result of differences in local
tissue perfusion. For example, the blood flow in the fingers of the
hand is greater than in alternative sites. This means that the
blood glucose in the fingertips will equilibrate more rapidly with
venous blood glucose concentrations. Furthermore, the magnitude of
differences in local glucose concentrations between two sites is
related to the rate of change in blood glucose concentrations.
Conversely, under steady-state glucose conditions, the glucose
concentration through-out the body tends to be uniform.
[0105] An additional study demonstrated that localized variations
in the glucose concentration in the dorsal versus volar aspect of
the forearm are small versus differences between the glucose
concentrations observed in either forearm region versus that of the
fingertip. J. Fischer, K. Hazen, M. Welch, L. Hockersmith, R
Guttridge, T. Ruchti, physiological differences between volar and
dorsal capillary forearm glucose concentrations and finger stick
glucose concentrations in diabetics, American Diabetes Association,
62.sup.nd Annual Meeting (Jun. 14, 2002).
[0106] Another study demonstrated very small localized variation in
glucose concentration within a region such as the dorsal aspect of
the forearm with observed differences approximating the scale of
the error observed in the reference method. The glucose
concentrations in the forearm are not observed to vary within three
inches laterally or axially from a central point of the
forearm.
[0107] In addition to differences in perfusion, the local
permeability of tissue to diffusion and the local uptake of glucose
during exercise or other activity can cause non-uniform
distribution of glucose in the body. Finally, when the noninvasive
variable and the reference glucose concentration are not measured
simultaneously, an additional error can occur when glucose is
varying in the body.
[0108] Physiology
[0109] The following physiological interpretations are deduced from
these studies:
[0110] during times of glucose change, the glucose concentration as
measured on the arm can lag behind that of the fingertip;
[0111] a well-recognized difference between the fingertip and the
forearm is the rate of blood flow;
[0112] differences in circulatory physiology of the off-finger test
sites may lead to differences in the measured blood glucose
concentration;
[0113] on average, the arm and finger glucose concentrations are
approximately the same, but the correlation is not one-to-one. This
suggests differences between traditional invasive glucose
concentrations and alternative invasive glucose concentrations are
different during time periods of fasting and after glucose
ingestion;
[0114] the relationship of forearm and thigh glucose levels to
finger glucose is affected by proximity to a meal. Meter forearm
and thigh results during the sixty and ninety minute postprandial
testing sessions are consistently lower than the corresponding
finger results;
[0115] differences are inversely related to the direction of blood
glucose concentration change;
[0116] rapid changes may produce significant differences in blood
glucose concentrations measured at the fingertip and forearm;
and
[0117] for individuals, the relationship between forearm and finger
blood glucose may be consistent. However, the magnitude of the
day-to-day differences has been found to vary. Finally,
interstitial fluid (ISF) may lead plasma glucose concentration in
the case of falling glucose levels due to exercise or glucose
uptake due to insulin.
[0118] Utilization of the Difference in Traditional Invasive and
Alternative Invasive Glucose Concentration
[0119] The discrepancy between the glucose level at the
non-invasive measurement site versus the reference concentration
presents a fundamental issue in relation to calibration. A
calibration is generally a mathematical model or curve that is used
to convert the noninvasively measured variable such as absorbance,
voltage, or intensity to an estimate of the glucose concentration.
Determination of the calibration is performed on the basis of a set
of paired data points composed of noninvasive variables and
associated reference blood glucose concentrations collected through
a blood draw. Any error introduced by the reference method is
propagated into any error associated with the indirect method as an
uncertain, imprecise, and/or biased calibration.
[0120] Method
[0121] The invention provides a method of developing a calibration
based on either traditional or alternate invasive reference glucose
measurements. The percentage error in the reference glucose
concentration is reduced through the application of one or more
techniques that improve correspondence between the reference
glucose concentration and the glucose concentration reflected in
the variable measured by the sensor, herein referred to as the
"sensor variable", thus producing a superior exemplary set of
calibration data for calculating the calibration curve or model.
Both noninvasive and implantable glucose analyzers require a
calibration because they rely on measurement of glucose indirectly
from a blood or tissue property, fluid, parameter, or variable.
While the target application is typically an optical sensor, any
device that measures glucose through a calibration falls within the
scope of the invention. Examples of such systems include:
[0122] near-infrared spectroscopy (700-2500 nm), O. Khalil,
Spectroscopic and clinical aspects of non-invasive glucose
measurements," Clin Chem, 45:165-77 (1999);
[0123] far-infrared spectroscopy;
[0124] mid-infrared spectroscopy;
[0125] Raman spectroscopy;
[0126] fluorescence spectroscopy;
[0127] spectroscillating thermal gradient spectrometry, P. Zheng,
C. Kramer, C. Barnes, J. Braig, B. Sterling, Noninvasive glucose
determination by oscillating thermal gradient spectrometry,
Diabetes Technology & Therapeutics, 2:1:17-25;
[0128] impedance based glucose determination;
[0129] nuclear magnetic resonance;
[0130] optical rotation of polarized light;
[0131] radio wave impedance;
[0132] fluid extraction from the skin;
[0133] glucose oxidase and enzymatic sensors;
[0134] interstitial fluid harvesting techniques (e.g. microporation
or application of a small electric current) or glucose electrode;
and
[0135] microdialysis.
[0136] As previously described, the calibration set constitutes a
set of paired data points collected on one or more subjects; and
generally includes glucose concentrations that span the expected
range of glucose variation. Each paired data point includes a
reference glucose value and an associated value or values of the
sensor variable.
[0137] The invented method relies on a variety of processes that
improve the reference values of the calibration set, which can be
used independently or together.
[0138] First is a process for calibrating using a calibration set
of paired data points including a reference glucose value from a
traditional invasive method or an alternative invasive method and a
noninvasive sensor measurement. This first process is based on the
recognition that glucose tends to be uniform throughout the tissue
under steady state conditions and that perfusion is the dominant
physiological process leading to differences in glucose under
dynamic situations. Within the context of this first process, a
number of techniques are suggested for improving reference values
with respect to their corresponding sensor values:
[0139] Paired data points are collected at intervals that allow
determination of the rate of glucose change. For example,
traditional invasive glucose determinations and noninvasive signals
may be generated every 15 minutes for a period of four hours. The
resulting calibration set is limited to paired data points with a
corresponding rate of glucose change less than a specified maximum
level.
[0140] Calibration data is collected during periods of stasis or
slow change in glucose concentration. The rate of acceptable change
in glucose concentration is determined on the basis of the
tolerable error in the reference values. For example, a rate of
change of 0.5 mg/dL/minute may be found to be acceptable;
[0141] Under dynamic conditions, the circulation at a measurement
site is perturbed, both for an alternative invasive measurement
site for calibration and later for measuring glucose utilizing an
alternative invasive glucose analyzer. Enhancement of circulation
in the forearm or alternate testing site, for example, causes the
local glucose concentrations to approach those of the fingertip. As
described above, methods for perturbing circulation may include
ultrasound, or a variety of surface applications that cause
vasodilatation, mechanical stimulation, partial vacuum, and
heating;
[0142] Patients are screened according to the discrepancy between
their traditional invasive glucose concentration at a fingertip or
toe and an alternative invasive glucose determination at the
alternative invasive site. For example, subjects with significant
discrepancy between the glucose concentration in the fingertip and
the local tissue volume sampled through a near-infrared device,
such as a forearm, would not be used for calibration. Subjects
having a small difference in glucose concentration between the
traditional invasive and alternative invasive measurement site
would be used for calibration. On this basis subjects are further
screened for device applicability for subsequent glucose
predictions; and
[0143] Using post-processing techniques, the sensor's estimate of
the glucose concentration is corrected. The method utilizes an
estimate of the time lead or lag between the two glucose
concentrations from a cross-correlation or time series analysis and
a correction using an interpolation procedure. A similar correction
would correct for a dampening of the noninvasive signal relative to
a traditional invasive signal.
[0144] In a second process, careful site selection assures that
reference values reflect the concentration of glucose in the sensor
variable. According to this process, blood, serum, plasma,
interstitial draws, or selective interstitial sample acquisitions
are taken from a tissue site that is either near the sensor sample
site or has been designed/determined to reflect the sample site.
For example, when noninvasive (sensor) near-infrared measurements
are taken for calibration on a forearm, it is possible in some
individuals to collect a capillary blood draw from an alternative
invasive sample site such as the same forearm or from the opposite
forearm. The blood draws are taken in a manner that maintains
perfusion equivalence to the noninvasive sample site.
[0145] It is noted that alternative invasive glucose determinations
acquire samples from varying depths. Some acquire interstitial
fluid from just below the epidermal later while others penetrate
into capillary blood or subcutaneous fluids. Because a noninvasive
glucose analyzer can be tuned to sense glucose concentrations from
different depths, a logical choice of a reference device is an
alternative invasive analyzer sampling from a similar depth in the
skin. For example, a near-IR glucose analyzer functioning in the
2100 to 2300, 1550 to 1800, or 1100 to 1350 nm region acquires
signal from approximately 1.5, 3, and 5 mm, respectively.
Similarly, a glucose analyzer functioning within 50 nm of 1450,
1900 or 2500 nm samples at depths of less than 1 mm. Hence,
noninvasive technologies that rely on tissue volumes primarily
including the epidermis indirectly measure primarily interstitial
glucose concentrations and may benefit from alternative invasive
glucose analyzers sampling the interstitial fluid from the
epidermis versus an alternative invasive glucose analyzer that
samples blood from the dermis.
[0146] Finally, glucose varies dynamically through time in
individuals. When a glucose determination through a blood or
interstitial sample cannot be taken simultaneously with the sensor
variable an error can exist due to the time differential. A
technique for reducing this error is based on interpolation and
extrapolation of the reference glucose values to the time the
sensor variable was collected.
[0147] Instrumentation
[0148] Noninvasive
[0149] A number of technologies have been reported for measuring
glucose noninvasively that involve the measurement of a tissue
related variable. Examples include but are not limited to
far-infrared absorbance spectroscopy, tissue impedance, Raman, and
fluorescence, as well as techniques using light from the
ultraviolet through the infrared [ultraviolet (200 to 400 nm),
visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000
cm.sup.-1), and infrared (2500 to 14,285 nm or 4000 to 700
cm.sup.-1)]. These techniques share the common characteristic that
they are indirect measurements of glucose. A calibration is
required in order to derive a glucose concentration from subsequent
collected data. In the past, capillary finger blood glucose and
venous blood glucose have been utilized to generate these
calibrations. However, as has been shown, these traditional
invasive glucose determinations do not always represent the glucose
concentration at the sampled site.
[0150] A number of spectrometer configurations are possible for
collecting noninvasive spectra of body regions. Typically, a
spectrometer, also called a sensor, has one or more beam paths from
a source to a detector. A light source may comprise a blackbody
source, a tungsten-halogen source, one or more LED's, or one or
more laser diodes. For multi-wavelength spectrometers a wavelength
selection device may be utilized or a series of optical filters may
be utilized for wavelength selection. Wavelength selection devices
comprise dispersive elements such as one or more plane, concave,
ruled, or holographic grating. Additional wavelength selective
devices include an interferometer, successive illumination of the
elements of an LED array, prisms, and wavelength selective filters.
However, variation of the source such as varying which LED or diode
is firing may be utilized. Detectors may in the form of one or more
single element detectors or one or more arrays or bundles of
detectors. Single element or array detectors maybe fabricated from
InGaAs, PbS, PbSe, Si, MCT (mercury-cadmium-tellurium), or the
like. Light collection optics such as fiber optics, lenses, and
mirrors are commonly utilized in various configurations within a
spectrometer to direct light from the source to the detector by way
of a sample. The mode of operation may be transmission, diffuse
reflectance, or transflectance. Due to changes in performance of
the overall spectrometer, reference wavelength standards are often
scanned. Typically, a wavelength standard is collected immediately
before or after the interrogation of the tissue, but may also occur
at times far removed such as when the spectrometer was originally
manufactured. A typical reference wavelength standard would be
polystyrene or a rare earth oxide such as holmium, erbium, or
dysprosium oxide.
[0151] The interface of the glucose analyzer to the tissue includes
a patient interface module and light such as near-infrared
radiation is directed to and from the tissue either directly or
through a light pipe, fiber-optics, a lens system, or a light
directing mirror system. The area of the tissue surface to which
near-infrared radiation is applied and the area of the tissue
surface the returning near-infrared radiation is detected from are
different and separated by a defined distance and their selection
is designed to enable targeting of a tissue volume conducive to
measurement of the property of interest. The patient interface
module may include an elbow rest, a wrist rest, and/or a guide to
assist in interfacing the illumination mechanism of choice and the
tissue of interest. Generally, an optical coupling fluid is placed
between the illumination mechanism and the tissue of interest to
minimize specular reflectance from the surface of the skin.
[0152] A preferred embodiment of the sensor 700, shown in FIG. 7,
is a spectroscopic measurement system that includes a tungsten
halogen near-infrared radiation source, a wavelength selection
filter 702 passing 1100 to 1900 nm light, fiber optics 703 for
conveying the source photons to an in-vivo skin sample, an
interface 704 to the forearm of a patient, fiber optic collection
optics 705 for gathering diffusely reflected and transflected
radiation from the skin to a grating, and an InGaAs array 706 to
detect the radiation, electronic means 707 for converting the
resulting signal into a glucose concentration and a display (not
shown). D. Klonoff, Noninvasive blood glucose monitoring, Diabetes
Care, 20:3:433 (March, 1997).
[0153] The sample site constitutes the point or area on the
subject's body surface the measurement probe contacts and the
specific tissue irradiated by the spectrometer system. Ideal
qualities for a sample site include: 1) homogeneity, 2)
immutability; and 3) accessibility to the target analyte.
Noninvasive glucose analyzers commonly use the fingertip as a
sampling site. However, several alternative sampling sites are
possible, including the abdomen, upper arm, thigh, hand (palm or
back of the hand) or ear lobe, in the preferred embodiment, the
volar part of the forearm is used. In addition, while the
measurement can be made in either diffuse reflectance or diffuse
transmittance mode, the preferred method is diffuse reflectance.
Scanning of the tissue can be done continuously when the tissue
area being tested is not affected by pulsation effects, or the
scanning can be done intermittently between pulses.
[0154] The collected signal (near-infrared radiation in this case)
is converted to a voltage and sampled through an analog-to-digital
converter for analysis on a microprocessor based system and the
result displayed.
[0155] Implantable:
[0156] In an alternate arrangement, the system or a portion of the
system is implanted, and the measurement is made directly on soft
tissue, muscle, a blood vessel or skin tissue within the body. In
this configuration, the measurement is made in a manner that is
non-invasive to the probed tissue although the system or a portion
of the system is implanted within the body. For example, the
peritoneal cavity is a suitable location for implantation and both
the probing signal source and detection system are implanted. In
the preferred embodiment, telemetry is employed to transfer data or
actual analyte readings to a remote location outside the body.
Alternately, a transcutaneous connector is employed. After
transfer, the data or concentration are then processed and
displayed to the user or heath care provider. Three different
embodiments of the implanted system are disclosed. The first, a
consumer version, is used for incremental or continuous
applications requiring intensive analysis of body analytes (e.g.,
glucose). A particularly useful application is nocturnal monitoring
of glucose and detection or prediction of hypoglycemic events. In
the second, the system is employed in a health care facility and
the analyte is monitored via a computer or health care provider. A
third embodiment of the implanted system is for use in a
closed-loop insulin delivery system. In this embodiment the system
is a sub-component of an artificial pancreas and used to monitor
glucose levels for insulin dosage determination via an insulin
pump.
[0157] In implantable embodiments, an alternative invasive or
noninvasive reference glucose concentration or set of
concentrations may be utilized with paired implantable signals in
order to calibrate an implantable glucose analyzer. This is
essentially the same as utilizing an alternative invasive glucose
analyzer to calibrate a noninvasive glucose analyzer as discussed
above. Utilization of an alternative invasive or noninvasive
reference is beneficial in instances when the implantable glucose
analyzer is sampling fluids or tissues that have perfusion similar
to that of the alternative invasive sites. For example, a
semi-implantable device may be placed into the subcutaneous tissue
or an implantable device may be placed into the peritoneal cavity.
Both of these regions may have dampened and lagged glucose
concentrations that are similar to alternative invasive glucose
determinations or noninvasive glucose determinations from regions
that are not well perfused. Hence, the reference values will more
closely represent the implantable signals. This will aid in
calibration design and maintenance as above.
[0158] Correction of Alternative Invasive to Traditional Invasive
Glucose Concentration
[0159] In building a glucose calibration model, a number of
measurement parameters must be considered. The selection of
measurement parameters will greatly affect predicted glucose
concentrations from subsequent spectra. For example, for glucose
determination based on near-IR spectral measurements, parameters
include sample selection, preprocessing step selection, and actual
model parameters such as the number of factors in a multivariate
model. In view of the demonstrated difference in glucose
concentration between traditional and alternative measurements,
selection of the appropriate set of glucose reference
concentrations is also important.
[0160] For example, a model may be based on a calibration set that
utilizes alternative invasive forearm glucose concentrations from
the dorsal aspect of the forearm and near-IR noninvasive glucose
determinations from the forearm. By using such a model to predict
glucose concentrations from subsequent spectra, the subsequent
measurements for a large number of subjects will correspond to the
values of the calibration set more closely than if the calibration
set were based on traditional invasive glucose determinations from
a fingertip. The importance of parameter selection is described in
greater detail below. Furthermore, a method for correcting
measurements based on a calibration set of traditional invasive
glucose determinations to approximate those based on a set of
alternative invasive determinations is provided.
EXAMPLE
[0161] A single calibration model was applied to 4,980 noninvasive
spectra collected from the volar aspect of the forearm of
twenty-six subjects covering 233 unique visits utilizing nine
instruments collected over a period of eight months. Each subject
was tested every fifteen minutes for a period of approximately
eight hours. The resulting glucose predictions were compared to
both traditional invasive reference fingertip and alternative
invasive reference forearm glucose concentrations.
[0162] A concentration correlation plot of the predicted glucose
concentrations versus the forearm reference glucose concentrations
is presented in FIG. 8. A Clarke error grid analysis for this data
demonstrates that 81.9 and 17.9 percent of the data falls into the
A and B region, respectively. Thus, 99.8 percent of the data are
predicted clinically accurately versus the alternative invasive
reference forearm glucose concentrations. However, as shown in FIG.
9, accuracy diminishes when plotted against the corresponding
traditional invasive reference fingertip glucose concentrations.
Clarke error grid analysis still results in 96.9% of the data in
the `A` or `B` regions; however, only 51.5% fall into the `A`
region. The correction methodology follows:
[0163] For each subject, lag of the predicted glucose concentration
versus reference glucose concentrations for both fingertip and
forearm determination is calculated. In order to account for the
difference between the predicted values and the reference, a phase
correction is calculated using a cross-covariance based algorithm
by sliding the x-axis (time vector) of the predicted values a fixed
amount to synchronize the predicted and reference values. A
histogram of the resultant lags is presented in FIG. 10. Lags for
the forearm are observed to range up to sixty-two minutes. The peak
of the lag for the comparison against the forearm and the fingertip
is approximately ten and 33.6 minutes, respectively. This indicates
that the model substantially tracks the forearm glucose
concentrations better than glucose concentrations from the
fingertip, a result of the model being built with forearm glucose
concentrations.
[0164] For each subject, a magnitude correction is calculated
comparing the predicted glucose concentrations to each of the
fingertip and forearm glucose concentration reference profiles. The
magnitude correction constitutes the difference between the glucose
concentration ranges of the predicted and reference values. It is
observed that the average difference between the predicted and
reference glucose concentrations is less for the forearm reference
glucose determinations than it is for the fingertip reference
glucose determinations. A ratio of the range of the predicted
values versus the range of the reference values is calculated for
each subject's visit. A histogram of the resulting ratios
representative of the magnitude difference is presented in FIG. 11.
The histogram demonstrates ratios closer to one for the forearm
glucose concentration range with peak values for the forearm and
fingertip of 0.71 and 0.55, respectively.
[0165] A third parameter not utilized in this particular model is a
correction of the frequency of glucose profile versus time. Thus,
the rate of glucose increase to a peak value and the rate of a
subsequent decline may differ for traditional invasive glucose
determinations and alternative invasive glucose determinations, and
this profile shape difference or period may be corrected.
[0166] It is here noted that specific examples of parameter
calculations are presented, but that those skilled in the art will
immediately appreciate that the lag, dampening, and frequency
parameters and similar parameters utilized to characterize
population differences may be calculated in a number of ways, any
of which are consistent with the spirit and scope of the invention.
For example, phase correction may be performed with techniques such
as a Bessel filter, warping of the time axis and re-sampling,
development of a wavelet-based model and subsequent time
compression, or shifting. Similarly, magnitude correction may be
performed with a simple multiplication factor after centering the
data to either the mean or single data point, a multiplication
factor dependent upon the rate of change, a multiplication factor
dependent upon time, a multiplication factor dependent upon the
tissue state, or a multiplication factor dependent upon the type of
diabetes or class of tissue. Additionally, it is noted that
incomplete vectors may still be utilized to determine these or
similar parameters.
[0167] A multi-step correction method may then be implemented
utilizing one or more of these parameters. In one example, a shift
correction is followed by a magnitude correction. First, the mean
shift value of 33.6 minutes is subtracted from the prediction time
vector. Second, a magnitude correction is performed. Initially, the
shift corrected data is mean centered. Then, the resulting glucose
concentrations are divided by 0.55. Finally, the mean of the shift
corrected data is added to the resulting vector of data.
[0168] The two-step correction with parameters of a shift
adjustment of 33.6 minutes and a scaling factor of 0.55 produced
above is here applied to a set of 7 daily visits from a total of 3
subjects representing noninvasive spectra collected from 3 near-IR
glucose analyzers. The fingertip reference glucose concentrations
and noninvasively predicted glucose concentration profiles are
presented in FIG. 12. The noninvasive glucose concentrations
predicted from spectra collected from the forearm are clearly
damped and lagged versus the corresponding traditional invasive
glucose determinations. The corresponding concentration correlation
plot overlaid with a Clarke error grid is presented in FIG. 13. The
algorithm corrected glucose profiles and corresponding
concentration correlation plot is presented in FIGS. 14 and 15,
respectively. Notably, the lag and dampening have been greatly
reduced. The respective statistics for the uncorrected and
corrected glucose concentrations reveal an obvious improvement in
accuracy. The statistics for the uncorrected and corrected glucose
concentrations are Clarke `A` region: 49.7 and 80.5%; r: 0.78 and
0.96, F-value: 2.38 and 10.9, standard error 54.4 and 26.0 mg/dL,
respectively.
[0169] The two-step correction demonstrated above was applied to
the entire data set. The corrected predicted fingertip glucose
concentrations are presented in a concentration correlation plot
superimposed onto a Clarke error grid, FIG. 16. The corrected
glucose concentrations result in 97.8% of the points falling into
the `A` or `B` region of the Clarke error grid. The correlation
coefficient, F-Value, and r value each showed a corresponding
increase. In addition, the algorithm allows conversion back and
forth between forearm and fingertip glucose concentrations.
[0170] While the preceding description has been directed primarily
to calibration sets that include invasive reference measurements,
embodiments of the invention are possible that employ noninvasive
reference measurements. The above data emphasize the importance of
taking reference measurements at a site having perfusion
equivalence to the sampling site. Accordingly, the principles
previously discussed are equally applicable to calibrations
developed using noninvasive reference measurements, rather than
invasive reference measurements.
[0171] Integrated Glucose Analyzer
[0172] An integrated glucose analyzer 1700 that utilizes
alternative invasive or traditional invasive glucose determinations
in combination with noninvasive measurements is shown in FIG.
17.
[0173] The invention includes a first component 1701 that measures
an analytical signal from the body to determine the body's glucose
concentration. Numerous noninvasive devices have been described
above. In one embodiment of the invention, a near-infrared
spectrometer configured for a noninvasive diffuse reflectance
measurement from the forearm may be utilized. The first component
1701 includes a control and processing element 1703 for executing
computer-readable instructions and at least one storage element
1704, such as a memory, having executable program code embodied
therein for converting a series of reflected near-IR signals,
collected from the forearm or other tissue site, into a
corresponding series of blood glucose values.
[0174] A second component 1702, that provides either a traditional
invasive or alternative glucose measurement, is electronically
coupled 1706a and b to the first component. Preferably, the second
component provides measurements having five percent error or
less.
[0175] The above program code also includes code for:
[0176] extracting the data from the traditional second component
1702;
[0177] storing the invasive blood glucose values extracted from the
second component 1702 in the storage element 1704 of the first
component 1701; and
[0178] using the stored invasive blood glucose values for
calibration, calibration assignment, validation, quality assurance
procedures, quality control procedures, adjustment, and/or bias
correction, depending on the current mode of operation.
[0179] For example, in the case of calibration, finger stick-based
blood glucose values are collected concurrently with noninvasive
spectra to form a calibration set of paired data points. The set is
used to calculate a mathematical model suitable for determination
of blood glucose on the basis of a noninvasive measurement, such as
a spectrum. As a second example, in the case of bias adjustment,
invasive blood glucose determinations are collected with the first
noninvasive glucose determination of the day and utilized to adjust
the noninvasive glucose concentration to the reference glucose
determination. The adjustment parameter is utilized until a new
invasive reference glucose determination is collected.
[0180] The above program code also includes code for:
[0181] providing a comparison and evaluation of the finger stick
blood glucose value to the blood glucose value obtained from the
noninvasive near-infrared diffuse reflectance measurement.
[0182] In one embodiment, information is communicated to the first
component 1701 from the second component 1702. Alternatively, the
second component 1702 may containing processing and storage
elements, instead of the first component. Noninvasive glucose
measurements are configured to operate in modes (transmission,
diffuse reflectance, and transflectance) as described above on body
parts as described above.
[0183] Finally, although the preferred embodiment employs
fingerstick measurements, any measurement having sufficient
accuracy and precision can be used as the reference
measurement.
[0184] There is a pronounced disadvantage to conventional systems,
in which a primary device and a secondary device are separate and
distinct from each other. Secondary measurements must be compared
to primary measurements, in order to validate the secondary
measurements. Conventionally, comparison requires the consumer to
manually input a blood glucose value from the primary device
(traditional or alternative invasive glucose analyzer) into the
secondary device (noninvasive or implantable glucose analyze) for
comparison. An inherent risk to such an approach is the improper
input of the primary glucose value into the secondary device, thus
resulting in an invalid comparison.
[0185] Advantageously, the integrated glucose analyzer eliminates
the necessity for the patient to manually input an invasive
measurement for comparison with the noninvasive measurement. A
second advantage is the ability to utilize a single case for both
components with a similar power supply and display. This results in
fewer elements that a person with diabetes need carry with them. An
additional advantage is a backup glucose analyzer in the event of
the noninvasive glucose analyzer failing to produce a glucose value
as may be the case with very high or hypoglycemic glucose
concentrations. A third advantage is traceability. The time
difference between a reference glucose determination from an
invasive meter and a corresponding noninvasive glucose reading may
be critical in establishing a correction to an algorithm such as a
bias. An automated transfer of the glucose value and the associated
time greatly reduces risks in usage of a noninvasive analyzer that
requires such a correction. Finally, the transfer of glucose and
time information into the noninvasive analyzer digital storage
means eases subsequent analysis and data management by the
individual or a professional.
[0186] This technology may be implemented in healthcare facilities
including, but not limited to: physician offices, hospitals,
clinics, and long-term healthcare facilities. In addition, this
technology would be implemented for home-use by consumers who
desire to monitor their blood glucose levels whether they suffer
from diabetes, impaired glucose tolerance, impaired insulin
response, or are healthy individuals.
[0187] Additionally, an embodiment is possible in which the first
and second components are separate analyzers, the first component
configured to measure glucose noninvasively, and the second
component configured to perform either alternate invasive or
traditional invasive measurements. In the current embodiment, first
and second components are electronically coupled by means of a
communication interface, such as RS232 or USB (universal serial
bus). Other commonly-known methods of interfacing electrical
components would also be suitable for the invention, such as
telemetry, infrared signals, radiowave, or other wireless
technologies. Either embodiment provides the above advantages of
eliminating the possibility of invalid measurements by doing away
with the necessity of manual data entry.
[0188] Although the invention has been described herein with
reference to certain preferred embodiments, one skilled in the art
will readily appreciate that other applications may be substituted
for those set forth herein without departing from the spirit and
scope of the present invention. Accordingly, the invention should
only be limited by the claims included below.
* * * * *