Sensitivity analysis of near infrared glucose absorption signals:

toward noninvasive blood glucose sensing

Vidi A. Saptari* and Kamal Youcef-Toumi
Department of Mechanical Engineering
Massachusetts Institute of Technology
Cambridge, MA 02139

ABSTRACT
Noninvasive blood glucose monitoring is a long pursued goal in clinical diagnostic. Among several other optical
methods, near infrared absorption spectroscopy is the most promising one for the noninvasive application to date.
However, realization has not been achieved. A major obstacle is the low signal-to-noise ratio pertinent to physiological
blood glucose measurement using the near infrared absorption technique. Sensitivity analysis of aqueous glucose
absorption signals was performed in the combination band region and in the first-overtone region. The analysis
involved quantification of both glucose absorption signal and the corresponding spectral noise within a particular
wavelength region. Glucose absorption band at 4430cm1 (2257nm) in the combination band region was found to give
an order of magnitude higher signal-to-noise ratio than the strongest band in the first-overtone region. A Fourier-
filtering algorithm was applied to the raw absorbance data to remove some of the unwanted spectral variations.
With simple peak-to-peak analysis to the Fourier-filtered absorbance data, repeatability of less than
was achieved. In addition, effects of temperature variations on the absorption spectra were studied. The effects of
sample temperature were compensated with the application of the Fourier filter.

Keywords: noninvasive, sensitivity, glucose, spectrocopy, infrared, absorption, fourier, blood, signal, noise

*Correspondence: E-mail: vidi©mit.edu; Telephone: 1-617-258-6785; Fax: 1-617-258-6575

Optical Techniques and Instrumentation for the Measurement of Blood Composition, Structure,
and Dynamics, Alexander V. Priezzhev, P. Ake Oberg, Editors, Proceedings of SPIE Vol. 4163 (2000) 45
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 1. INTRODUCTION
Noninvasive blood glucose monitoring is a long pursued goal in clinical diagnostic as an invaluable tool that would
aid in the treatment of diabetes. Pain, inconvenience and cost have hindered the effectiveness of the current "finger
prick" technique to monitor and control blood glucose level in diabetics. The benefits of close control of physiological
glucose level have been proven through clinical trials, which include reduced risks of complications' and prolonged
life.2
Among several other optical methods, near-infrared absorption spectroscopy has been demonstrated to be the
most promising one to date. Despite tremendous amount of research for the past several years, there has not been
any breakthrough that would enable the realization of a practical and reliable noninvasive glucose monitoring system.
The problems that have prohibited the success of this technique can be summarized into two main categories: low
signal-to-noise ratio and measurement irreproducibility.
Physiological glucose concentration changes in the blood produce little quantifiable absorption optical signal.
The signal due to glucose changes can sometimes be of lower magnitude than the noise and errors introduced by the
measuring instrument itself. Thus, signal-to-noise ratio (SNR) is low. In addition, variations in tissue and blood
properties, measurement procedures, as well as inter-individual variations lead to irreproducible results. This is
because the spectral changes due to these variations can be larger than the spectral changes due to glucose variations
in the blood.
Figure 1 shows a schematic representation of glucose optical sensor as a system, where the input is the optical
signal due to glucose absorption and the output is the prediction signal, usually in the form of digital data. It
can be considered as consisting of two main modules: the hardware and the software. The hardware includes a
spectrometer, photo-detectors, A/D converters, a computer, among others. The software includes post-processing
and/or calibration algorithms. As the schematic suggests, there are two main sources of noise: instrumental and
physiological. Instrumental noise includes errors introduced by each of the hardware components, for example,
detector noise, digitization noise and light source fluctuations. Physiological noise includes variations such as tissue
temperature, skin humidity and blood hemoglobin level changes.

N oi sephysiological N th sehardw are

Sign

light source filtering

spectrom eter calibration
detector
A/D converter, etc

Figure 1. System level schematic of a noninvasive optical-based glucose sensor

Most of the efforts in this research area have been focused on the software, which is mainly in the development
of mathematical algorithms in the form of " calibration" techniques to extract spectral information due to glucose
variations and suppress spectral noise and other unwanted variations3'4'5'6'7 . They involve taking a sufficiently
large amount of data from measurements of known glucose concentration values and building calibration algorithms
to fit the data. Although this is an important and necessary operation, the importance of understanding the origins
and characteristics of both the noise and the signal is often overlooked. Particularly, comprehension of hardware
limitations deserves more attention as it is known that the instrument often introduces noise much higher than the
glucose signal. Depending on the characteristics of the noise, the post-processing algorithms may not be able to
suppress it.
In this project, we take a somewhat different approach. We put significant effort on instrumental limitations
understanding as well instrumental optimization through the development of a custom near infrared Fourier transform
spectrometer.8 In this paper, the SNRs of two near-infrared glucose absorption bands in the first-overtone region

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 and in the combination band region are evaluated through sensitivity analysis. The analysis involves quantifying
the signal produced by each mmol/L glucose change and the spectral noise in a particular band region. Method
prospects and limitations are discussed. In addition, sample temperature effects on the near infrared spectra are
studied. The study shows the importance of understanding the noise characteristics for the success of noise removal
through post-processing.
1.1. Definition of signal-to-noise ratio of absorption spectra
Most of the absorption measurements employ single-beam technique, which involves taking the ratio of the trans-
mission or the reflectance spectra of the sample and the reference measured at two different times. In keeping with
the convention, the absorption signal can be defined as

Tsampie(vi)
A(v) = —loge (1)
( T reference (ii) )
where A(v) is the absorption peak at wavenumber zi, Tsampie 5 the transmission spectrum of the sample and
Treference 5 the transmission spectrum of the reference. The reference could be an air background spectrum or the
spectrum of a pure buffer.
Therefore, in the single-beam absorption spectroscopy, measurement repeatability is of prime importance. In other
words, in-between-measurement errors have to be small compared with the absorption signal intensity. For example,
if the absorption intensity of the sample of interest is one absorption unit (AU) , the measurement uncertainties (or
the absorption spectral noise) has to be significantly less than one AU. Comparison between spectral noise and the
absorption intensity is usually apparent in qualitative measurements, where the presence and clarity of the absorption
peaks are all that need to be observed.
In quantitative studies, however, more careful analysis needs to be done to determine the ratio of the signal to
the noise. In these studies, signal intensity is related to the resolution of the sample concentration change to be
achieved. For a smaller step of concentration change to be observed, the signal intensity that needs to be recorded
will be lower. This is apparent from the Beer Lambert's law, which states that the absorption signal intensity is
linearly related to the path-length and the concentration, as indicated in eqn.(2),

A(v) = c(v)cl, (2)

where c is the absorptivity coefficient (sample property), c is the concentration and 1 is the path-length of the
radiation in sample. In order to differentiate smaller change in concentration &, smaller needs to be observed.
An appropriate manner to measure the spectral noise N, which is a measure of spectral repeatability, is given by

N(ii) = -loge
(:) .

Ta and Tb are transmission spectra of the same buffer (for example, pure water) taken at two different times, usually
(3)

back-to-back, as shown in figure 2. Note that ideally, N is a flat line at zero across the wavenumbers. This is the
case where there is zero noise, or the measurement is perfectly repeatable. The root-mean-square (RMS) value of
the spectral noise NRMS in a particular wavelength region is computed as

Nrms Nj2, (4)

where n is the number of spectral elements being observed. Note that the RMS value is usually three to five times
smaller than the peak-to-peak noise value. The SNR can then be computed as,

SNR= A(v) (5)

NRMS
In our quantitative glucose measurements, A(v) is usually defined as the absorption intensity for a certain mmol/L
change in glucose concentration. Spectral noise and signal-to-noise ratio assessment is pictorially illustrated in figure
2.

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 0
E
0

W avenumber (cm ') W avenumber (cm )

Figure 2. Left: transmission spectra of two same buffers. Right: illustration of absorption spectral noise and
signal-to-noise ratio evaluation in single-beam spectroscopy measurements.

1.2. Effects of water absorption characteristics on spectral SNR

Because water is the main component of blood, absorption spectrum of water plays an important role in determining
the availability of certain wavelength regions for glucose measurement. In certain regions, water absorbs too strongly,
which results in extremely low radiation energy transmitted through. As a result, spectral SNR in these regions is
low. This is due to the fact that detector noise, which is usually the main contributor of noise in the case of low
radiation, is independent of the signal. Thus, low signal results in low SNR. Mid-infrared wavelength region has this
characteristic, which leaves it "worthless" for quantitative analysis involving aqueous media, including blood and
tissue.
Figure 3 shows the transmission spectrum of water between 2500cm' and 7500cm' (l300nm and 4000nrn).
The water was placed in a 2mm path-length quartz cuvette. A long-wave-pass filter was used as indicated in the
diagram to exclude the transmitted visible light. This is necessary because the transmission in the visible region is
much higher than that in the near infrared. Without the intereference filter, water transmission spectrum in the
near infrared will not be clearly observable.

Blocked by optical

Figure 3. Near infrared transmission spectrum of water in a 2mm path-length quartz cuvette

As seen in figure 3, there are two near infrared regions where water has relatively higher tranmittance. One is
between 5400cm1 and 6400cm' (1560nm and l85Onrn) and the other is between 4300cm' and 4800cm' (2080nm

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 and 2325nm) . In association with glucose absorption measurements, the former is usually called the first-overtone
region and the later is usually called the combination band region. The names arise from the origins of the molecular
vibrations in these regions.2 Because of the relatively higher water transmission, they represent useful "windows"
for quantitative analysis involving aqueous media. Note also that the transmission intensity in the first-overtone
region is about seven times stronger than in the combination band region, which means that the later potentially
has larger spectral noise.
In this paper, we present the analysis of glucose absorption bands in these two regions. We have also looked at
glucose absorption bands in the shorter wavelength. Although spectral noise is lower in these regions (because of
high water transmittance) , glucose absorption signals, which are due to the higher overtone vibrations, are extremely
low. Thus, they are of little values.

2. SENSITIVITY ANALYSIS OF NIR GLUCOSE ABSORPTION BANDS

2.1. Materials and methods
Anhydrous D-glucose were dissolved in distilled water, with concentration levels spanned between 3mmol/L and
lOOmmol/L. Except for glucose solutions greater than 32mmol/L, glucose concentrations were determined using a
commercial electrode-based sensor, Glucometer Elite, manufactured by Bayer Corporation, USA. Due to the limited
range of sensor, the higher concentration glucose solutions were prepared simply by using their mass-molar relation.
All solutions were stored in room temperature. No sample temperature control was done during the experiments.
Experiments were performed in a transmission configuration, where the transmitted radiation was measured.
Samples were placed in a 2mm path-length quartz cuvette. Investigations of the first-overtone and the combination
band regions were done separately, each with its own appropriate filter to isolate only the region of interest. Long-
wave-pass filters at l500nm (6667cm') and 2000nm (5000cm') were used for the first-overtone and the combination
region respectively. This was important to ensure optimization of the use of dynamic range of the photo-detector
and the analog-to-digital converter.8 Significant loss in SNR can occur as a result of negligence in this particular
experimental procedure. Natural absorption due to water eliminated the need for short-wave-pass filters for both
cases as seen in figure 3.
For the first-overtone region, seven different glucose concentration values spanned between 3.5mmol/L and
lOOmmol/L were measured. Each value of the concentration was measured twice, which consisted of three steps.
First, a transmission spectrum of glucose solution of a particular concentration was measured. Second, transmis-
sion spectrum of pure water was obtained. Third, we repeated the measurement of the glucose solution with the
same concentration as in the first step. Thus, evaluations of seven concentration values consisted of twenty-one
measurements. Measurements were done in random with respect to concentration. Similar steps were used for the
combination band region. In this case, nine different glucose concentration values spanned between 3.5mmol/L and
32 mmol/L were analyzed, which resulted in a total of twenty-seven measurements.
Absorption spectral noise was assessed by measuring ten water transmission spectra back-to-back for each band
region. In each region, nine absorbance noise spectra from the tansmission spectra were produced by referencing a
spectrum to the immediate previous one, as illustrated by eqn.(3). Noise value was calculated for the wavenumbers
between 5850cm1 and 6000cm' (1667nm and l7lOnm) for the first-overtone region and between 4350cm1 and
4500cm' (2222nm and 2299nm)for the combination band region, about a third-order fit to account for the baseline
variations.
All measurements were done using a custom-built Fourier transform spectrometer designed for the near infrared
quantitative studies.8 The light source was a 100W tungsten-halogen lamp, which contains radiation from 350nm
to 2500nm. The power source was a deep-cycle 12V battery to ensure stable radiation output. Calcium fluoride
beamsplitter and lenses were used due to its high throughput in the near infrared region. The photodetector was a
two-stage thermo-electrically cooled InGaAs detector (J18TE2-66G-RO1M-2.6, EG&G Judson), responsive between
3846cm' and 12500cm' (800nm and 2600nm).
Each measurement consisted of a double-sided, 4001 interferogram points based on co-adding 200 scans. A
triangular apodization function and 3000-point zero fillings were applied to each tail of the averaged interferogram.
It was then Fourier transformed to produce a spectrum with 6.3cm' point spacing. To minimize the effects of
low-resolution baseline variations and higher-resolution noise, digital Fourier filtering was applied to the absorbance
spectra9'4 . For this purpose, a Gaussian-shaped filter was applied, with its center location determined by the

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 equivalent width criterion.10 The width of the filter was determined experimentally by analyzing its effect on several
glucose absorbance spectra. All data processings were done in Matlab.
2.2. Results and discussions
In the near infrared region alone, glucose has multiple absorption bands of different absorption strengths,7 due
to their different absorptivity coefficients, defined in eqn.(2). The purpose of the sensitivity analysis is to identify
the critical absorption band for glucose concentration prediction. This involves not only the determination of the
absorption strength but also the noise level. Thus, the aim is to quantify the signal-to-noise ratio achievable in a
particular band region.
As figure 3 suggests, there are two near infrared regions that can be used for glucose analysis, namely the first-
overtone region and the combination band region. In the first-overtone region, glucose absorption band at around
5940cm' (1684nm) is observed to be the strongest. This agrees with the results obtained by Arnold et.al.7 This band
has been assigned as a CH overtone band.2 Five raw absorption spectra of aqueous glucose solutions of different
glucose concentrations are illustrated in figure 4. As seen in the figure on the left, large baseline variations mask
glucose peaks except for the highest concentration, which is at lOOmmol/L. The application of the digital Fourier
filter removes these variations and improves the spectral features that correlate with glucose concentration in the
aqueous solutions, as depicted in figure on the right.
In the combination band region, the strongest band is observed to be at around 4430cm'(2257nm). This
absorption band is probably due to combination of CH stretch and OCH deformation.2 The raw absorbance spectra
and the Fourier-filtered absorbance spectra of aqueous glucose solutions in this band region are depicted in figure
5. Similar to the results of the first-overtone region, the raw absorbance spectra in the combination region are of
little value for glucose concentration prediction mainly due to their large baseline variations. The Fourier filtered
absorbance spectra, however, have strong correlation to the glucose concentrations.

x iø-

5860 5880 5900 5920 5940 5960 5980 6000 6020 6040
Wavenumber (cm-') Wavenumber (cm-')

Figure 4. Absorption spectra of aqueous glucose solutions in the first-overtone region. Left: raw absorption spectra.
Right: Fourier-filtered absorption spectra
To quantify the correlation of the filtered spectrum and its corresponding glucose concentration, simple peak-to-
peak assessment was performed. For the first-overtone band, the filtered absorbance magnitude was calculated to be
the maximum peak height at around 5940cm' minus the midpoint of the two minimum values of the valley around
5885cm' and around 6000cm' . Similarly for the combination band region, the filtered absorbance magnitude was
calculated to be the maximum peak height at around 4430cm' minus the midpoint of the two minimum values of
the valley around 4380em' and around 4480cm'. Simple algorithms were used to perform this evaluation, and
are illustrated in eqn. (6) and eqn. (7) for the first-overtone and the combination band region respectively.

—to—peak Min[A(5885 20cm')] + Min{A(6000 20cm1)]

= Max{A(5940 20cm')] ______________________________________________________
filtered 2 (6)

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 x iô3
0- J
,
27mM
-0.5 - --

165mM
-1.5
=
-2 - -- --- 84mM

-2.5

-3 125m?4-

-as
-4 -- -
-4_s ----
4350 4400 4450 4500 4550 4380 4400 4420 4440 4460 4-480 4500
Wavenumber (cm') Wavenumber (cm-')

Figure 5. Absorption spectra of aqueous glucose solutions in the combination band region. Left: raw absorption
spectra. Right: Fourier-filtered absorption spectra

20cm')] + Min[A(4480 20cm1)]

A:pe Max{A(4430 20cm')J — Min[A(4380 2 (7)

Figure 6 shows how these values change as a function of glucose concentration for both the first-overtone band
and the combination band. For both cases, the magnitude of the absorbance seem to vary linearly with glucose
concentration. The rate of change is approximately 2.3 x 1O_6 per mmol/L for the first-overtone region, and 3. 1 x iO
per mmol/L for the combination band region. Thus, the Fourier filtered glucose absorption signal intensity in the
4430cm1 band is 13.5 higher than in the 5940cm' band. Note however that these are not the true absorbance
values due to the application of the digital Fourier filter. With carefull analysis, the true absorbance value was
estimated to be twice the filtered value for the first-overtone band and 2.6 times as high for the combination band.
Another thing to infer from figure 6 is that the repeatability in the combination band is much better than what is
achievable in the first-overtone band. This can be seen from how close the two absorbance values from the same
concentrations are with each other.

,,

8 tO

= 8
=
= 0
'.5
0 00
8

0
0 0
0.5 0 8°
00 8 8
8

_o 10 20 30 40 50 60 70 80 90 100 880 0 5 tO 5 20 25 30 35

Glucose Concentration (mmol/L) Glucose Concentration (mmol/L)

Figure 6. Fourier-filtered peak absorbance as a function of glucose concentration. Left: first-overtone region. Right:
combination band region

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 To quantify the achievable signal-to-noise ratio, the spectral noise within each band was computed as well. The
RMS noise value was measured to be 1.9 x i05 x iO AU for the first-overtone band and 2.0 x iO 1.0 x iO
AU for the combination band. Thus, as illustrated in eqn.(5), SNR was calculated to be the absorbance value for
each mmol/L change in glucose concentration divided by the root-mean-square value of the spectral noise. The
achievable SNRs were 0.24 and 4.0 for the first-overtone band and the combination band respectively.
Table 1 summarizes the results for the sensitivity analysis. Comparison between the absorption signal intensity
and the noise value enables computation of signal-to-noise ratio attainable. The analysis showed that glucose absorp-
tion band centered at around 4430cm' in the combination band region, gave an order of magnitude improvement
in sensitivity over absorption band at around 5940cm' in the first-overtone region. Using digital Fourier-filtering
technique and simple peak-to-peak absorbance measurement in the combination band region, the achievable repeata-
bility with 2mm aqueous glucose optical path-length was found to be less than +O.5mmol/L. This value is deduced
from the right plot in fig.6, where the worst irreprducibility is 1.5AU, which translates to of
glucose concentration. This analysis thus suggests that the glucose absorption band at around 4430cm' is a critical
absorption band for glucose concentration prediction.

Peak RMS noise Filtered Absorbance SNR Absorptivity a

wavenumber absorbance per mmol/L per mmol/L (mm mmol/L1
per mmol/L change
5940cm' (l.9J.5)x1O5 2.3x106 4.6x106 0.24 2.3xl06
4430cm' (2.0±1 .O)x105 3.1 x10 8.Oxl 0 4.0 4.0x105

Table 1. Summary of sensitivity analysis results

3. REMOVING SPECTRAL NOISE DUE TO TEMPERATURE VARIATIONS

It has been widely known that sample temperature variation can greatly affect the near infrared absorption spec-
tra11 '12 Spectral changes due to temperature changes can be of much higher magnitude than the sample absorbance
signal itself. This is especially true in the measurements of clinically relevant glucose concentration. However, here we
show that through the application of the Fourier filter algorithm, temperature effects on the absorption spectra can
be greatly reduced. Arnold et. al.'3 performed similar study where temperature effects were compensated through
the combination of Fourier filter and partial least-squares regression to the spectra between 4000cm' and 5000cm'.
In our study, we adhered to simple peak-to-peak analysis of Fourier-filtered data in one glucose absorption band at
4430 75cm'.
The left picture in figure 7 shows the raw absorbance spectra of water at -' 40°C and two 32mmol/L glucose
solutions at 25°C and -' 40°C referenced to water at -' 25°C. As seen in the figure, temperature variations create
large base-line variations. Since these spectral variations are of much lower resolution than the resolution of the
glucose absorption signal, Fourier filtering may be able to eliminate them. This is indeed true, as can be seen from
the filtered absorbance spectra shown on the right in figure 7. The two glucose spectra appear very close to each
other, as they should, since they are of the same concentration value. The filtered water absorbance spectrum, which
can be considered as spectral noise N(zi) as defined by eqn. (3) , is close to zero for a wide range of wavenumbers.
This result suggests that sample temperature control may not be needed in the near infrared aqueous glucose
absorption measurements. This study also suggests the possibility of other physiological noise removal through the
post-processing algorithm. However, the knowledge of noise characteristics is an important prerequisite.

4. DISCUSSIONS AND CONCLUSIONS

Glucose absorption band at 4430cm' in the combination band region has been identified to be critical for aqueous
glucose measurement in the clinically relevant concentration range. This is due to the high glucose absorptivity in
this region, which is an order of magnitude higher than the absorptivity in the first-overtone region. In this region,
however, water absorbs stronger, thus leaving less radiation transmitted through. For the in vitro experiments
performed, this did not result in lower spectral SNR, as it would if detector noise was the dominant source of noise.

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 0.025
12 Glucose
Water40C 40C
10
0.02

Glucose
0.015 - - - _40pc 6

40C
0.01

0
0.005 Glucose
25CC

0 -4

4300 4350 4400 4450 4500 4550 4600 4360 4380 4400 4420 4440 4460 4480 4500

w avenumber (cm1) W avenumber (cm)

Figure 7. Left: spectral variations due to sample temperature changes. Right: removal of temperature effects
through Fourier filtering. Note: glucose concentration: 32mmol/L

In the case of noninvasive applications, the radiation would most likely need to penetrate through a tissue.
Tissue property variations may create spectral variations, which may be larger than the signal from glucose changes.
Therefore, measurements may not be repeatable. Careful studies need to be done to understand the characteristics
of the spectral noise due to each tissue variation. As demonstrated in the case of temperature effects, some may be
eliminated or compensated through the post-processing algorithms.
In addition to the irreproducibility due to tissue variations, the radiation that can be collected would be much
lower in intensity due to the additional scattering and absorption that take place in the tissue. It is likely that the
signal would be low enough such that detector noise becomes the dominant source of noise. When this is the case,
spectral signal-to-noise ratio or the achievable sensitivity would decrease in proportion to the decrease in signal.
More efforts need to be put in careful investigations of the effects of tissue to the spectral noise, and finally to the
achievable signal-to-noise ratio, before realization of a reliable noninvasive glucose sensor is possible.

ACKNOWLEDGEMENTS
The authors greatly appreciate the financial support provided by the Home Automation & Health Care Consortium.
In addition, the authors are indebted to Professor Ian Hunter and Dr.Colin Brenan of MIT for the invaluable
discussions and suggestions.

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