WO1999043255A1 - Near infrared-transmission spectroscopy of tongue tissue - Google Patents

Near infrared-transmission spectroscopy of tongue tissue Download PDF

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Publication number
WO1999043255A1
WO1999043255A1 PCT/US1999/004054 US9904054W WO9943255A1 WO 1999043255 A1 WO1999043255 A1 WO 1999043255A1 US 9904054 W US9904054 W US 9904054W WO 9943255 A1 WO9943255 A1 WO 9943255A1
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Prior art keywords
tongue
spectra
glucose
fat
measurement
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PCT/US1999/004054
Other languages
French (fr)
Inventor
Gary W. Small
Jason J. Burmeister
Mark A. Arnold
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University Of Iowa Research Foundation
Ohio University
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Application filed by University Of Iowa Research Foundation, Ohio University filed Critical University Of Iowa Research Foundation
Priority to AU33110/99A priority Critical patent/AU3311099A/en
Publication of WO1999043255A1 publication Critical patent/WO1999043255A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/01Measuring temperature of body parts ; Diagnostic temperature sensing, e.g. for malignant or inflamed tissue

Definitions

  • This application relates to the non-invasive measurement and monitoring of chemical substances found in blood, and particularly to the non-invasive measurement and monitoring of blood glucose levels.
  • the present invention overcomes the difficulties of prior art processes by using transmission spectroscopy, and by performing the measurements on the tongue of the - 2 -
  • NIR near infra red
  • Fig. 1 shows SEP versus noise plots for model data sets. Vertical lines indicate noise levels of the webbing (solid) and tongue (dashed) for back to back spectra at different measurement wavelengths.
  • Figs. 2A-F show absorbance spectra for near-infrared measurements at different measurement sites.
  • Fig. 3 shows single beam spectra of human webbing (dashed) and tongue (solid) with a glucose absorbance spectrum (dotted) overlaid.
  • Figs. 4 A and B show 100% lines of back-to-back psectra of human webbing and tongue with an absorbance spectrum of 1M glucose overlaid.
  • Figs. 5 A-E show glucose concentrations versus sample number for the calibration samples for five individuals.
  • Figs. 6 A-D show SEP versus RMA noise calculated over 100 cm "1 spectral ranges for model data sets. Circles and triangles are 5.6 and 6.3 mm aqueous thickness without scatter, respectively. Squares are prediction errors from the model data set with scattering particles added. The vertical lines are noise levels of subject D who had an aqueous layer thickness of 5.5 mm.
  • Figs. 7A-E are concentration correlation plots for the best PLS models for the five volunteers predicting the blind samples.
  • Figs. 8A-E are concentration plots for the five volunteers, using the first sample as the calibration and the last samples as the prediction. - 3 -
  • non-invasive monitoring of glucose in a human patient is carried out by measuring the near infrared absorbance of glucose using transmission spectroscopy on the tongue of the human patient.
  • This selection of measurement site provides better correlation with invasive measurements than non-invasive measurements performed at other sites, including the index fmger and webbing of the hand.
  • EXAMPLE 1 Evaluation of Alternative Measurement Sites Spectra were collected on a modified Midac spectrometer for the near infrared range. Modification include laser detectors, a fan designed to control temperature in the spectrometer, a 250-Watt source operating at about 110 watts and a one-millimeter diameter InGaAs detector with a 1.9 ⁇ m cutoff (Epitaxx). An H-band astronomical filter was used to limit the source bandpass to utilize the full dynamic range of the detector without saturation and minimize sample heating. A one-inch diameter, 25 mm focal length convex lens was used to focus the source intensity on the sample or fiber optic bundle.
  • tissue spectra before converting it to absorbance tissue spectra before converting it to absorbance
  • the detector and mount were fixed in the spectrometer in a vertical position for the tongue spectra and in a horizontal position for
  • beef fat was 2.4 mm for a webbing thickness of 6 mm.
  • Table 1 lists RMS noise levels
  • Figure 1 shows plots of SEP versus RMS noise levels for various frequency ranges for
  • Table 2 lists the calculated aqueous and fat thicknesses.
  • Spectra were collected through the tongue of various people.
  • the average thickness of fat and water was 0.2 and 5.9 mm, respectively, for the 10 volunteers who
  • Figure 3 shows single beam spectra of the human tongue and webbing
  • Table 1 also shows noise levels of tongue spectra calculated in the hospital with
  • Spectra were collected using a Midac M-Series spectrometer modified for the
  • the thickness of the sample was confined to 5.45 mm.
  • the first 189 spectra were not included because the source voltage varied and
  • model parameters were optimized. Three unique rearrangements of calibration and monitoring sets were used to optimize spectral range and number of PLS factors. The parameters which gave the lowest average SEM for all three rearrangements of calibration and monitoring were selected. This procedure reduces the chance of over modeling and modeling information specific to a single small monitoring set .
  • Figure 5 shows plots of glucose versus
  • Table 3 shows the correlation coefficient (r 2 ) of the time profiles.
  • glucose concentrations are believed to be representative of the blood glucose variation for these individuals. Significant spectral and concentration changes are needed to build
  • noise levels were calculated using a second order polynomial fit for 100% lines from
  • the ratio of the intensity at 5751 to 6994 cm '1 is the intensity at the fat band divided by the intensity at the peak of the single
  • the signal to noise (SNR) is the peak single beam intensity divided
  • SD/mean intensity is the standard deviation of the peak single beam intensities divided by
  • the in vitro model was used to estimate ideal prediction errors for the noninvasive data set.
  • the aqueous layer thickness was estimated to be about 5.5 mm.
  • Figure 7 A-E are concentration correlation plots for the best
  • Table 5 Optimal PLS parameters and prediction errors from predicting blind samples.
  • SEP a includes all data in blind
  • SEPb excludes circled data * SEP is greater than SDC - 14 -
  • the model for subject E is predicting the mean concentration.
  • the first is spectral noise from the detector and other electronic and optical components
  • This noise is related to the number of photons at a given frequency
  • the in vitro model of a aqueous and fat layer of constant thickness produces this type of noise.
  • the other type of noise is variation of strongly absorbing components such as fat and muscle.
  • composition or movement during the data collection is a composition or movement during the data collection.
  • the concentration correlation plot for subject E illustrates a situation where all
  • an improved design for the interface may improve

Abstract

Non-invasive measurement of blood glucose levels is carried out using transmission spectroscopy on the tongue of the individual. The near infrared (NIR) first overtone spectral region between 7000 and 5000 cm-1 (1.43 - 2 νm) is well suited for non-invasive measurements. Because the tongue is one of the leanest accessible sights in the body, variations in readings due to body fat are minimal. Further, the tongue is well thermostated and vasculated which are important factors in selecting a measurement site.

Description

WO 99/43255 . \ . PCT/US99/04054
NEAR INFRARED-TRANSMISSION SPECTROSCOPY OF TONGUE TISSUE
DESCRIPTION Background of the Invention
This application relates to the non-invasive measurement and monitoring of chemical substances found in blood, and particularly to the non-invasive measurement and monitoring of blood glucose levels.
Diabetes affects approximately 16 million people in the United States. People suffering from diabetes mellitus must monitor their blood glucose levels for insulin replacement therapy. At present, this generally requires an invasive procedure, performed several times daily, in which a sample of blood is taken for analysis. Non-invasive procedures have been proposed, including those found in US Patents Nos. 5,069,229 and 5,459,317, and EP 0 548 418, which are incorporated herein by reference, but no in-home non-invasive glucose measurement device is as yet available.
Among the proposals for non-invasive measurement of blood chemicals are those which depend on diffuse-reflectance of infrared radiation, for example from a fmger, lip or forearm. In these techniques, light is delivered to the surface of the tissue, penetrates for some distance and then is reflected back to be detected. The drawback of the diffuse reflectance measurements is that the depth to which the light penetrates is not deep enough to have enough interaction with glucose to provide consistent and quantitative detection of glucose. In addition, tissue areas conventionally used for diffuse reflectance measurements may have varying amounts of fat from individual to individual. Since fat interferes with detection of glucose, this variability can make calibration and quantification difficult.
It is an object of the present invention to provide an improved method for the non-invasive measurement of glucose.
Summary of The Invention
The present invention overcomes the difficulties of prior art processes by using transmission spectroscopy, and by performing the measurements on the tongue of the - 2 -
individual. The near infra red (NIR) first overtone spectral region between 7000 and 5000 cm"1 (1.43 - 2 μm) is well suited for non-invasive measurements. Because the tongue is one of the leanest accessible sights in the body, variations in readings due to body fat are minimal. Further, the tongue is well thermostated and vasculated which are important factors in selecting' a measurement site.
Brief Description of the Drawings
Fig. 1 shows SEP versus noise plots for model data sets. Vertical lines indicate noise levels of the webbing (solid) and tongue (dashed) for back to back spectra at different measurement wavelengths.
Figs. 2A-F show absorbance spectra for near-infrared measurements at different measurement sites.
Fig. 3 shows single beam spectra of human webbing (dashed) and tongue (solid) with a glucose absorbance spectrum (dotted) overlaid.
Figs. 4 A and B show 100% lines of back-to-back psectra of human webbing and tongue with an absorbance spectrum of 1M glucose overlaid.
Figs. 5 A-E show glucose concentrations versus sample number for the calibration samples for five individuals.
Figs. 6 A-D show SEP versus RMA noise calculated over 100 cm"1 spectral ranges for model data sets. Circles and triangles are 5.6 and 6.3 mm aqueous thickness without scatter, respectively. Squares are prediction errors from the model data set with scattering particles added. The vertical lines are noise levels of subject D who had an aqueous layer thickness of 5.5 mm.
Figs. 7A-E are concentration correlation plots for the best PLS models for the five volunteers predicting the blind samples.
Figs. 8A-E are concentration plots for the five volunteers, using the first sample as the calibration and the last samples as the prediction. - 3 -
Detailed Description of the Invention
In accordance with the present invention, non-invasive monitoring of glucose in a human patient, is carried out by measuring the near infrared absorbance of glucose using transmission spectroscopy on the tongue of the human patient. This selection of measurement site provides better correlation with invasive measurements than non-invasive measurements performed at other sites, including the index fmger and webbing of the hand.
In selecting a site for non-invasive glucose determination, several factors need to be considered. First, a useful technique needs to produce results which are reliable predictors of the actual glucose levels. Second, it would be desirable to have a calibration model which would work in substantially all patients. Patient-to-patient variation in the physical size of the tissue being measured and in the levels of interferents such as fats, which can act as a major interferent in the measurement of glucose in the overtone region, can make achieving these goals a complicated process. Our evaluation of several alternative measurement sites, however, indicates that the tongue is a highly suitable location for non- invasive glucose measurements.
To evaluate various sites for their suitability, single beam transmission spectra were collected of human webbing between the thumb and forefinger, tongue, nasal septum, cheek, upper lip and lower lip. As described below, the hand webbing had the highest levels of fat in the individuals tested, thus producing the worst results, while the tongue had the lowest fat levels and produced the most accurate and reproducible results.
- 4 -
EXAMPLE 1 Evaluation of Alternative Measurement Sites Spectra were collected on a modified Midac spectrometer for the near infrared range. Modification include laser detectors, a fan designed to control temperature in the spectrometer, a 250-Watt source operating at about 110 watts and a one-millimeter diameter InGaAs detector with a 1.9 μm cutoff (Epitaxx). An H-band astronomical filter was used to limit the source bandpass to utilize the full dynamic range of the detector without saturation and minimize sample heating. A one-inch diameter, 25 mm focal length convex lens was used to focus the source intensity on the sample or fiber optic bundle.
Preliminary single beam spectra were collected using a fiber optic bundle olan
Jenner Industries) connected to the thickness controlling window to direct the incident
radiation to the sampling site. The detector and mount was freed from the spectrometer
for ease of sampling. This arrangement allowed spectra to be collected from hard to
reach body sites. Single beam transmission spectra were collected of human webbing
between the thumb and forefinger, tongue, nasal septum, cheek, upper lip, and lower lip.
A background single beam spectrum was collected without a sample in the optical path
using a combination of a neutral density filter to limit the incident source intensity and a
low detector preamplifier gain setting to avoid detector and electronic saturation. The air
spectrum was corrected to match the higher gain and incident radiation intensity of the
tissue spectra before converting it to absorbance.
Spectra with lower noise levels were collected without the fiber optic bundle to
maximize incident source intensity. The detector and mount were fixed in the spectrometer in a vertical position for the tongue spectra and in a horizontal position for
the webbing spectra. A mirror was used to direct the incident radiation to the detector for
the tongue spectra. - 5 -
Absorption spectra of the webbing of 19 volunteers were collected. A regression
analysis was performed to compute the thickness of water and fat from the spectra using
beef fat and water as the standards. The average thickness of water was 4.67 mm and
beef fat was 2.4 mm for a webbing thickness of 6 mm. Table 1 lists RMS noise levels
for various frequency ranges of ten back-to-back webbing spectra of 128 scans each.
Figure 1 shows plots of SEP versus RMS noise levels for various frequency ranges for
model spectra consisting of a constant fat thickness of 1.6 mm and variable water thicknesses of 5.6 and 6.2 mm. From Figure 1 and Table 1 , a very high SEP would
be expected if the webbing were used (greater than 3 mM). The RMS noise levels are
low in the spectral region which is dominated by water absorbance (>6000 cm"1). The
noise levels in the region dominated by fat absorbance are very high. They are an order
of magnitude higher than the model spectra. Between measurement variations in the amount of fat compressed within the light path have not been successfully controlled.
Another body site for the noninvasive measurement is needed because of the strong
overlap between the absorbance bands of fat and glucose.
Table 1 RMS noise values calculated from webbing and tongue 100% lines.
Spectral Range (cm"1) 6400 6300 6200 6100 6000 5900
Sample -6300 -6200 -6100 -6000 -5900 -5800
6 mm webbing 54.7 25.1 18.0 36.1 271.1 605.8 5.5 mm tongue 96.7 47.7 25.4 18.0 56.6 68.1 - 6
The composition and physical thickness of several bodily sites were evaluated with the goal of finding a suitable site for a noninvasivc measurement of glucose. Absorption spectra are listed in Figures 2A through 2F. It is apparent from the
spectra that the upper and lower lips, tongue, cheek and nasal septum have less fat than
the webbing. A regression analysis was performed to quantify the amount of fat and
aqueous thickness. Table 2 lists the calculated aqueous and fat thicknesses. The
tongue was found to be most desirable because it has the least amount of fat and there are
relatively few variations between people. Major disadvantages of the tongue are the
possibility of spreading disease while sampling many people and the discomfort of
collecting spectra.
Table 2 Calculated aqueous and fat thicknesses obtained from regression analysis.
Sample Thickness Aqueous thickness Fat thickness Scatter (mm) (mm) (mm)
Webbing 5.75 4.91 2.62 1.56
Upper lip 6 5.91 0.48 1.72
Lower lip 6 5.95 0.65 1.84
Tongue 6 5.61 0.26 1.47
Nasal septum 6 5.86 0.51 1.81
Check 6 5.61 0.37 1.61
Figure imgf000008_0001
- 7 -
Spectra were collected through the tongue of various people. The average thickness of fat and water was 0.2 and 5.9 mm, respectively, for the 10 volunteers who
were sampled. Figure 3 shows single beam spectra of the human tongue and webbing
collected under the same instrumental configuration with a superimposed absorbance
spectrum of 1.0 M glucose. Although the spectrometer alignment was not held constant,
the spectrum of the tongue is less absorbing and has less fat. Figure 4 shows 100%
lines of back-to-back spectra of the human webbing and also from human tongue. Large
variations in the fat bands which overlap with the glucose bands at 5920 and 5750 cm' in
the webbing spectra makes it obvious that the tongue is a superior measurement site. Table 1 also shows noise levels of tongue spectra calculated in the hospital with
multiple interfaces. From these noise levels and .Figure 2 one may estimate a SEP of
about 2 mM on a one subject study.
It is clear that the tongue is a superior measurement site for a noninvasive
measurement compared to the webbing. The convenience of collecting spectra through
the webbing of the hand is traded for lower variations in the amount of fat within the light
path. The interface between the spectrometer and the volunteer will need to be sterilized
between collecting spectra from different subjects. If the same spectral quality were
obtained in a noninvasive data collection as the test spectra from the tongue a SEP of about 2 could be obtained. - 8 -
EXAMPLE 2 Detection of Blood Glucose Levels Using Transmission Spectroscopy of The Tongue
Spectra were collected over the course of 39 days on five type 1 diabetic
volunteers, 3 female and 2 male. The experimental procedure was approved by a human
subject protocol board at the University of Iowa Hospitals and Clinics. Two spectra and
one reference blood glucose concentration were collected for each volunteer's visit which
numbered greater than 100. The number of visits per day were limited to less than five
per volunteer.
Spectra were collected using a Midac M-Series spectrometer modified for the
NIR. The spectrometer modifications are detailed in Chapter 8. The source was held at
81.0 watts by supplying constant voltage. An H-band astronomical filter was used to
limit the bandpass of the source intensity. The 1-mm diameter 1.9 μm cutoff InGaAs
detector (Epitaxx) was held at 15 °C by supplying constant voltage to a thermal electric
cooler. The resistor in the feedback loop of the first stage of the detector preamplifier
was 27.1 kΩ. Interferograms (8K) were collected, Fourier transformed, and the resulting
single beam spectra with a data spacing of 4 cm"1 were saved over the spectral range
between 7000 and 5000 cm"1. The temperature of the interface was held at 38.5 °C using
a DC heating element and a temperature control circuit. The temperature was monitored
at the following cites during the course of each data collection: room, interface, and
inside the spectrometer. - 9 -
Five interchangeable stainless steel interfaces were machined. These consisted of
a cylindrical sheath to cover the detector and an adjustable lever which controls the sample thickness. Each piece had a hole machined through with a 1 1.5-mm diameter
circular sapphire window to allow the source radiation to pass through the sample to be
detected. The thickness of the sample was confined to 5.45 mm. The interchangeable
interfaces were swabbed with 95% ethanol and autoclaved at 130 °C for 5 minutes
between volunteer visits.
Reference Blood Glucose Values
Capillary blood from a finger stick was drawn into a 100 μL volume heparinized
tube. These samples were analyzed immediately with a YSI 2300 Stat Plus glucose
analyzer (Yellow Springs Instruments) with both probes measuring glucose. These
reference values were validated with a simultaneous measurement using a One-touch test
strip capillary blood glucose analyzer. The average of two YSI glucose values was used
to build PLS models. Every fifth blood sample was considered a 'blind' and was not used
to optimize the PLS models.
Data Analysis
Separate PLS models were optimized using single beam spectra from each
individual. The first 189 spectra were not included because the source voltage varied and
the volunteers were learning how to perform the measurement in this time period.
Spectra were also removed if their single beam intensity was very low. A PCA score analysis was performed but no spectral outliers were removed. The PLS calibration - 10 -
model parameters were optimized. Three unique rearrangements of calibration and monitoring sets were used to optimize spectral range and number of PLS factors. The parameters which gave the lowest average SEM for all three rearrangements of calibration and monitoring were selected. This procedure reduces the chance of over modeling and modeling information specific to a single small monitoring set .
Concentration Correlations
By limiting the number of samples that were collected each day, the correlation
between glucose and time was minimized. Figure 5 shows plots of glucose versus
sample number for the calibration samples for the five subjects. They look like scatter
plots. Table 3 shows the correlation coefficient (r2) of the time profiles. The
correlation coefficients are all below 0.014. It is not likely that any temperature variation
or spectrometer drift correlated with these randomized concentrations. In this way,
spectral variations that the PLS models are built upon should only be analyte specif tiicc changes.
Table 3 Description of glucose concentrations.
subject number high low mean standard deviation Regression coefficcnts of time plots (mM) (mM) (mM) (mM) Bo B, R2
A 173 21.3 2.94 9.91 4.53 8.904 0.01082 0.01377
B 178 28.3 2.54 12.64 6.67 12.13 0.006442 2.465c-3
C 181 19.1 2.83 9.05 4.06 12.62 -2.203e-4 6.085c-6
D 207 26.85 3.20 1 1.88 5.09 8.625 5.032c-3 4.245c-3
E 169 16.75 3.79 8.57 2.83 8.793 -8.642c-4 2.020c-4
Figure imgf000012_0001
- 11 -
Significant glucose concentration variation is seen in all subjects except volunteer
E who has very tight control over her glycemia. Table 3 ijsts the high, low, mean, and
standard deviation of each subject's sample concentrations as well as the total number of
spectra. The subjects were not persuaded to vary their daily diabetes treatments. The
glucose concentrations are believed to be representative of the blood glucose variation for these individuals. Significant spectral and concentration changes are needed to build
meaningful PLS calibration models. The limited concentration range for volunteer E
might make calibration difficult.
Spectral Quality The spectral quality is fairly high. Table 4 lists RMS noise levels calculated
over 100 cm"1 intervals, the standard deviation of the ratio of the intensity at 5751 to 6994 cm' , standard deviation of the single beam intensity, and signal to noise ratio. The RMS
noise levels were calculated using a second order polynomial fit for 100% lines from
back-to-back single beam spectra. The noise levels between 6100 and 6000 cm'1 are
fairly low but the noise levels between 6000 and 5900 cm"1 are not as low as those
collected on the author in the pre-experiment trial. The ratio of the intensity at 5751 to 6994 cm'1 is the intensity at the fat band divided by the intensity at the peak of the single
beam, respectively. The signal to noise (SNR) is the peak single beam intensity divided
by the RMS noise of the single beam calculated between 7000 and 6800 cm'1. The
SD/mean intensity is the standard deviation of the peak single beam intensities divided by
the mean peak intensity multiplied by 100%. - 12 -
Comparison to Model
The in vitro model was used to estimate ideal prediction errors for the noninvasive data set. The aqueous layer thickness was estimated to be about 5.5 mm. By comparing
the noninvasive noise levels to Figure 6 ; jt was estimated that an SEP of about 2.3 M
would be the best that could be expected for the noninvasive data if there were no
interferences and no variation in the amount of fat in the optical path. The vertical lines
are the noise levels from subject D. The SEP estimate for the 6000-5900 cm"1 plot is
found by drawing a line between the models with and without scattering particles.
Table 4 Description of noninvasive spectral quality.
Subject 6100-6000 6000-5900 SD Intensity SD/mean SNR
(μA.U.) (μA.U.) (5751/5994 cm"1) intcnsity(%) (xlO4)
A 26.9 95.1 0.007191 7.71 4.2 B 28.0 88.3 0.009485 8.08 3.5 C 26.6 89.8 0.005072 8.34 4.2 D 24.5 82.0 0.006365 9.64 3.9 E
Figure imgf000014_0001
31.1 99.1 0.011918 9.62 3.7 13
Predicting Blind Samples The calibration data set was used to predict the blind samples using the optimal
PLS parameters. Figure 7 A-E are concentration correlation plots for the best
PLS models for the volunteers predicting the blind samples. The circled points are
spectra in the blind that are not within the scatter of the calibration data. The circled
point for volunteer D at about 1 1 mM was had the highest normalized intensity at 5943 cm"1 which is where protein absorbs. The circled point for volunteer C at 19 mM is the
highest concentration sample in the data set. There seems to be a bias of under predicting
high concentration samples. This bias was also observed in monitoring sets. The best SEP's are 2.70 and 2.66 for volunteers D and C with the high concentration samples
removed, respectively.
Table 5 Optimal PLS parameters and prediction errors from predicting blind samples.
Who Range Factors SEC SEP. SEPb SDP (oV) (mM) (mM) (mM) (mM)
A 6510-5600 1 1 3.51 3.48 4.41
B 6310-5550 1 1 4.29 7.56* 5.50 6.75
C 6600-5650 1 1 3.04 3.49 2.66 3.73
D 6550-5620 16 2.52 3.96 2.70 4.69
E 6600-5650 10 2.62 3.35* 2.74
Figure imgf000015_0001
SEPa includes all data in blind
SEPb excludes circled data * SEP is greater than SDC - 14 -
In Figure 7B for subject B one point is not shown. The model predicted a blind
sample at 48.9 M when the actual concentration was 16.5 mM. The SEP without this
point is 5.50 mM. The model for subject E is predicting the mean concentration., The
slope is actually negative for this concentration correlation plot (Figure >7E). Even though the model has no prediction, 88% of the prediction points are in the A and B
regions due to the limited concentration range of this subject. ' Table 6 lists the SEC,
SEP, regression analysis and percentage of predicted samples in each of the regions on the Clarke error grid.
Table 6 Prediction errors and Clarke error grid analysis of predicting blind samples.
subject SEC SEP SDP Regression Analysis % of prediction in Clarke error grid Regions
( M) ( M) (mM) ol" Prediction Data
Bo B, R2 A B C D E
A 3.51 3.48 4.41 4.031 0.5466 0.4333 54.1 37.8 8.1 0 0
B 4.29 7.56* 6.75 10.01 0.3393 0.1 198 28.9 52.6 13.2 5.3 0
C 3.04 3.49 3.73 5.423 0.3710 0.2274 43.2 51.4 0 5.4 0
D 2.52 3.96 4.69 5.992 0.4543 0.3136 53.7 34.1 4.9 7.3 0
E 2.62 3.35* 2.74 8.778 -0.05689 0.0156744.1
Figure imgf000016_0001
44.1 0 11.8 0
- 15 -
Predicting Last Part of Data In a real world situation for in-home or clinical devices there will be an initial data
collection used to build the calibration set. The model must be robust so it can accurately
predict the concentrations of spectra following the initial calibration. Predicting the blind
samples which were every fifth sample throughout the entire data collection is unrealistic
in that there is a calibration sample before and after each blind sample. Spectrometer or
temperature drifts could be more easily accounted for in this situation. To approximate a
real world calibration, spectra from the beginning of the data collection were used as the
calibration and spectra from the end of the data collection were predicted. The same PLS parameters used to predict the blind samples were used. Figures 8A through E are
concentration correlation plots of the five volunteers using the first samples as the
calibration and the last samples as the prediction. Table 7 shows details of the data
sets and model performance.
Table 7 Prediction errors and Clarke error grid analysis of predicting last part of data.
subject SEC SEP SDP Regression Analysis of % of prediction in Clarke error grid Regions
Prediction Data (mM) (mM) (mM) B0 B, R2 A B C D E
A 3.27 4.42 4.72 7.562 0.2623 0.1643 26.9 55.8 5.8 11.5 0
B 4.77 6.08 6.58 10.69 0.2379 0.3129 17.6 52.9 20.6 2.9 5.9
C 2.96 3.86 4.1 1 8.027 0.3358 0.3067 40.7 50 5.6 1.9 1.9
D 2.73 3.35 5.44 4.1 19 0.6930 0.6303 54.2 35.4 2.1 10.4 0
Figure imgf000017_0001
E 2.71 2.72 2.66 8.577 0.06652 0.02379 43.8
Figure imgf000017_0002
5 566..22 0 0 0 - 16 -
In the noninvasive spectra there arc two sources of RMS noise on 100% lines.
The first is spectral noise from the detector and other electronic and optical components
of the spectrometer. This noise is related to the number of photons at a given frequency
which are detected by the detector. The in vitro model of a aqueous and fat layer of constant thickness produces this type of noise. The other type of noise is variation of strongly absorbing components such as fat and muscle. Although the noninvasive spectra
have low noise in the spectral region dominated by water absorbance (greater than 6000 cm"1), there are variations in the fat and muscle bands (below 6000 cm"1 ) which are
believed to be causing our high prediction errors. Subject E who had the worst PLS
model had the highest variation in the fat band. This variation could be related to body
composition or movement during the data collection.
The concentration correlation plot for subject E illustrates a situation where all
predictions are in the A and B regions on the Clarke error grid but the model is clearly
void of any analytical utility. This shows that the Clarke error grid alone is insufficient to judge analytical performance of PLS models.
Although, it is debatable whether glucose is being modeled for subjects A, B, and
C. There is very strong evidence that glucose is being modeled for subject D. There is a
bias of under predicting high concentration spectra. If this were due to a lack of
analytical information the lower concentrations would be over predicted as with subject
E. This is not the case. The predictions at low concentrations actually follow the unity
line. It has been reported that there is a time delay in the increase of interstitial glucose
concentration when blood glucose concentration is rising. When light passes through - 17 -
thc tongue it is believed that the majority of the photons will interact with interstitial fluid
not blood. The mismatch between our predicted glucose values and reference blood
glucose values at high concentrations accounts for scatter at high concentrations. There arc conflicting claims in the literature about the exact relationship between blood and interstitial glucose concentrations. If the lower interstitial glucose docs not track blood
glucose at high concentrations, it would be further evidence that we are actually
measuring glucose. This has never been observed before and is further evidence that we
are measuring glucose absorbance information.
For the first time, a human noninvasive blood glucose measurement has been demonstrated. The calibration was uch that glucose concentration was independent of sample order which eliminates the possibility of falsely low prediction errors due to
chance correlations between glucose concentration and temperature or spectrometer drift.
A real world calibration where data collected initially was used to predict data collected at
a later time yielded similar prediction errors as predicting the blind samples which were
every fifth sample throughout the data set.
For future measurements, an improved design for the interface may improve
spectral reproducibiiity, thereby, reducing prediction errors. Also, the source power could
be increased by at least 50% which would yield a higher signal to noise ratio. Although,
spectral quality was probably compromised, the two-month data collection better approximates real world situations compared to calibrations over the course of one week.

Claims

1. A method for non-invasive monitoring of glucose in a human patient, comprising measuring the near infrared absorbance of glucose using transmission spectroscopy, wherein the measurement is performed on the tongue of the human patient.
2. The method of claim 1 , wherein the near infrared absrobance is measured in the first overtone spectral region between 7000 and 5000 cm"1.
PCT/US1999/004054 1998-02-25 1999-02-25 Near infrared-transmission spectroscopy of tongue tissue WO1999043255A1 (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001063251A1 (en) * 2000-02-25 2001-08-30 Instrumentation Metrics, Inc. A non-invasive method of determining skin thickness and characterizing layers of skin tissue in vivo
WO2003087759A2 (en) 2002-04-04 2003-10-23 Inlight Solutions, Inc. Non-invasive spectroscopic measurement of analytes using a matched reference analyte
US6816605B2 (en) 1999-10-08 2004-11-09 Lumidigm, Inc. Methods and systems for biometric identification of individuals using linear optical spectroscopy
US8125623B2 (en) 2006-09-29 2012-02-28 Ottawa Hospital Research Institute Correlation technique for analysis of clinical condition
CN105628481A (en) * 2015-12-03 2016-06-01 浙江大学 Device for preparing tissue oximeter calibrating standard liquid and calibration method
US9487398B2 (en) 1997-06-09 2016-11-08 Hid Global Corporation Apparatus and method of biometric determination using specialized optical spectroscopy systems
CN110384507A (en) * 2019-07-16 2019-10-29 西安石油大学 A kind of detection method based on lip optics woundless measurement of blood sugar concentration

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5070874A (en) * 1990-01-30 1991-12-10 Biocontrol Technology, Inc. Non-invasive determination of glucose concentration in body of patients
US5692504A (en) * 1993-11-04 1997-12-02 Boehringer Mannheim Gmbh Method and apparatus for the analysis of glucose in a biological matrix

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5070874A (en) * 1990-01-30 1991-12-10 Biocontrol Technology, Inc. Non-invasive determination of glucose concentration in body of patients
US5692504A (en) * 1993-11-04 1997-12-02 Boehringer Mannheim Gmbh Method and apparatus for the analysis of glucose in a biological matrix

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9487398B2 (en) 1997-06-09 2016-11-08 Hid Global Corporation Apparatus and method of biometric determination using specialized optical spectroscopy systems
US6456870B1 (en) 1999-07-22 2002-09-24 Sensys Medical, Inc. Non-invasive method of determining skin thickness and characterizing layers of skin tissue in vivo
US6816605B2 (en) 1999-10-08 2004-11-09 Lumidigm, Inc. Methods and systems for biometric identification of individuals using linear optical spectroscopy
WO2001063251A1 (en) * 2000-02-25 2001-08-30 Instrumentation Metrics, Inc. A non-invasive method of determining skin thickness and characterizing layers of skin tissue in vivo
WO2003087759A2 (en) 2002-04-04 2003-10-23 Inlight Solutions, Inc. Non-invasive spectroscopic measurement of analytes using a matched reference analyte
US8125623B2 (en) 2006-09-29 2012-02-28 Ottawa Hospital Research Institute Correlation technique for analysis of clinical condition
CN105628481A (en) * 2015-12-03 2016-06-01 浙江大学 Device for preparing tissue oximeter calibrating standard liquid and calibration method
CN110384507A (en) * 2019-07-16 2019-10-29 西安石油大学 A kind of detection method based on lip optics woundless measurement of blood sugar concentration
CN110384507B (en) * 2019-07-16 2022-03-18 西安石油大学 Detection method for non-invasive measurement of blood glucose concentration based on lip optics

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