U.S. patent application number 13/145927 was filed with the patent office on 2015-07-30 for system for noninvasive determination of alcohol in tissue.
The applicant listed for this patent is Bentley Laaksonen, Mike Mills, Trent Ridder, Ben Ver Steeg. Invention is credited to Bentley Laaksonen, Mike Mills, Trent Ridder, Ben Ver Steeg.
Application Number | 20150208983 13/145927 |
Document ID | / |
Family ID | 42356227 |
Filed Date | 2015-07-30 |
United States Patent
Application |
20150208983 |
Kind Code |
A9 |
Ridder; Trent ; et
al. |
July 30, 2015 |
SYSTEM FOR NONINVASIVE DETERMINATION OF ALCOHOL IN TISSUE
Abstract
An apparatus and method for non-invasive determination of
attributes of human tissue by quantitative infrared spectroscopy to
clinically relevant levels of precision and accuracy. The system
includes subsystems optimized to contend with the complexities of
the tissue spectrum, high signal- to-noise ratio and photometric
accuracy requirements, tissue sampling errors, calibration
maintenance problems, and calibration transfer problems. The
subsystems include an illumination/modulation subsystem, a tissue
sampling subsystem, a calibration maintenance subsystem, an FTIR
spectrometer subsystem, a data acquisition subsystem, and a
computing subsystem.
Inventors: |
Ridder; Trent; (Woodbridge,
VA) ; Ver Steeg; Ben; (Redlands, CA) ; Mills;
Mike; (Tijeras, NM) ; Laaksonen; Bentley;
(Albuquerque, NM) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ridder; Trent
Ver Steeg; Ben
Mills; Mike
Laaksonen; Bentley |
Woodbridge
Redlands
Tijeras
Albuquerque |
VA
CA
NM
NM |
US
US
US
US |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20110282167 A1 |
November 17, 2011 |
|
|
Family ID: |
42356227 |
Appl. No.: |
13/145927 |
Filed: |
January 23, 2010 |
PCT Filed: |
January 23, 2010 |
PCT NO: |
PCT/US10/21898 PCKC 00 |
371 Date: |
July 22, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12562050 |
Sep 17, 2009 |
8174394 |
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13145927 |
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11515565 |
Sep 5, 2006 |
7616123 |
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12562050 |
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61147107 |
Jan 25, 2009 |
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Current U.S.
Class: |
600/314 ;
600/322 |
Current CPC
Class: |
A61B 5/4845 20130101;
G01J 3/14 20130101; G01N 21/474 20130101; G01J 3/0218 20130101;
G01J 3/0205 20130101; A61B 5/6826 20130101; G01J 3/02 20130101;
G01N 21/274 20130101; G01J 3/0291 20130101; G01N 2201/129 20130101;
G01J 3/0229 20130101; A61B 5/0075 20130101; G01N 21/359 20130101;
A61B 5/1495 20130101; A61B 5/14546 20130101; G01J 2003/1286
20130101; A61B 5/0088 20130101; A61B 5/1455 20130101 |
International
Class: |
A61B 5/1455 20060101
A61B005/1455; A61B 5/145 20060101 A61B005/145 |
Claims
1. An apparatus for determining an analyte property of a sample,
comprising: a. An illumination subsystem comprising a semiconductor
light source; b. A sampling subsystem, mounted with the
illumination subsystem such that light from the illumination
subsystem is directed to a sample by the sampling subsystem; c. A
data acquisition subsystem, mounted with the sampling subsystem
such that light from the sample is communicated from the sampling
subsystem to the data acquisition subsystem; d. A computing
subsystem, mounted with the data acquisition subsystem such that
the computing subsystem can determine the analyte property from
information from the data acquisition subsystem.
2. An apparatus as in claim 1, wherein the sampling subsystem
comprises an interface to in vivo tissue.
3. An apparatus as in claim 2, wherein the interface to in vivo
tissue comprises an interface to tissue of a human hand.
4. An apparatus as in claim 3, wherein the interface to tissue of a
human hand comprises an interface to tissue on the top of one or
more fingers between the first and second knuckles thereof.
5. An apparatus as in claim 1, wherein the illumination subsystem
comprises a plurality of semiconductor light sources.
6. An apparatus as in claim 5, wherein the output of the plurality
of semiconductor light sources is optically combined before
communication to the sample.
7. An apparatus as in claim 5, wherein the output of the plurality
of semiconductor light sources is homogenized spatially, angularly,
or both, before communication to the spectrometer.
8. An apparatus as in claim 5, wherein each semiconductor light
source is characterized by a center wavelength different from the
center wavelengths of other of the plurality of semiconductor light
sources.
9. An apparatus as in claim 8, wherein each semiconductor light
source is modulated at a modulation frequency different than the
modulation frequency of other of the plurality of semiconductor
light sources.
10. An apparatus as in claim 9, wherein the modulation is according
to one or more of Fourier, Hadamard, Fishers, z transform,
sinusoidal, square, and triangular wave modulation.
11. An apparatus as in claim 9, wherein the correspondence of
semiconductor light source to modulation frequency is random.
12. An apparatus as in claim 9, wherein the modulation is performed
by one or more of controlling drive voltage of the semiconductor
light source, controlling drive current of the semiconductor light
source, controlling drive power of the semiconductor light source,
controlling a mechanical mask mounted with the illumination
subsystem, controlling an optical mask mounted with the
illumination subsystem, controlling a filter wheel mounted with the
illumination subsystem, controlling a chopper wheel mounted with
the illumination subsystem, controlling an electrically controlled
optical component mounted with the illumination subsystem,
controlling a liquid crystal device mounted with the illumination
subsystem, controlling a digital mirror device mounted with the
illumination subsystem, controlling an acouto-optic tunable filter
mounted with the illumination subsystem.
13. An apparatus as in claim 1, wherein the semiconductor light
source comprises at least one of VCSEL, diode laser, quantum
cascade laser, quantum dot laser, LED, HCSEL, organic LED.
14. An apparatus as in claim 1, wherein at least one of the drive
current, drive voltage, drive power, and temperature of the
semiconductor light source is stabilized.
15. An apparatus as in claim 1, wherein at least one of the
emission wavelength and emission profile of the semiconductor light
source is tuned by controlling at least one of drive voltage, drive
current, drive power, or temperature of the semiconductor light
source.
16. An apparatus as in claim 7, wherein the light is homogenized by
at least one of a light pipe and a diffuser.
17. An apparatus as in claim 1, wherein the analyte property is at
least one of: concentration of one or more analytes, presence of
one or more analytes, direction of change of concentration of one
or more analytes, rate of change of concentration of one or more
analytes, and presence of one or more interferents that tend to
cause errors in the measurement of one or more other analyte
properties.
18. An apparatus as in claim 2, wherein the analyte property is at
least one of: concentration of one or more analytes, presence of
one or more analytes, direction of change of concentration of one
or more analytes, rate of change of concentration of one or more
analytes, presence of one or more interferents that tend to cause
errors in the measurement of one or more other analyte properties,
and a biometric property of the tissue.
19. A method of determining an analyte property in a human,
comprising a. Providing an apparatus as in claim 2; b. Using the
apparatus to determine optical properties of tissue of the human;
c. Using the computing subsystem to determine the analyte
property.
20. A method as in claim 19, wherein the computing subsystem uses
information from previous interactions with the apparatus in
combination with information from the present interaction with the
apparatus in the determination of the analyte property.
21. A method as in claim 19, wherein the computing subsystem does
not use information from previous interactions with the apparatus
in combination with information from the present interaction with
the apparatus in the determination of the analyte property.
22. A method as in claim 19, wherein the analyte property is at
least one of: concentration of one or more analytes, presence of
one or more analytes, direction of change of concentration of one
or more analytes, rate of change of concentration of one or more
analytes, presence of one or more interferents that tend to cause
errors in the measurement of one or more other analyte properties,
and a biometric property of the tissue.
23. A method as in claim 22, wherein the analyte property is at
least two of: concentration of one or more analytes, presence of
one or more analytes, direction of change of concentration of one
or more analytes, rate of change of concentration of one or more
analytes, presence of one or more interferents that tend to cause
errors in the measurement of one or more other analyte properties,
and a biometric property of the tissue.
24. A method as in claim 22, wherein the analyte is at least one
of: alcohol, alcohol byproducts, alcohol markers, and alcohol
adducts.
25. A method as in claim 19, wherein the analyte property comprises
both determination of an analyte concentration and determination of
a biometric property.
26. (canceled)
27. (canceled)
28. (canceled)
29. (canceled)
30. An apparatus as in claim 1, wherein the sampling subsystem
communicates light to the sample at a plurality of distinct regions
of the sample.
31. An apparatus as in claim 1, wherein the sampling subsystem
collects light from a plurality of distinct regions of the sample.
Description
FIELD OF THE INVENTION
[0001] The present invention generally relates to a quantitative
spectroscopy system for measuring the presence or concentration of
alcohol, alcohol byproducts, alcohol adducts, or substances of
abuse utilizing non-invasive techniques in combination with
multivariate analysis.
BACKGROUND OF THE INVENTION
[0002] Current practice for alcohol measurements is based upon
either blood measurements or breath testing. Blood measurements
define the gold standard for determining alcohol intoxication
levels. However, blood measurements require either a venous or
capillary sample and involve significant handling precautions in
order to minimize health risks. Once extracted, the blood sample
must be properly labeled and transported to a clinical laboratory
or other suitable location where a clinical gas chromatograph is
typically used to measure the blood alcohol level. Due to the
invasiveness of the procedure and the amount of sample handling
involved, blood alcohol measurements are usually limited to
critical situations such as for traffic accidents, violations where
the suspect requests this type of test, and accidents where
injuries are involved.
[0003] Because it is less invasive, breath testing is more commonly
encountered in the field. In breath testing, the subject must
expire air into the instrument for a sufficient time and volume to
achieve a stable breath flow that originates from the alveoli deep
within the lungs. The device then measures the alcohol content in
the air, which is related to blood alcohol through a breath-blood
partition coefficient. The blood-breath partition coefficient used
in the United States is 2100 (implied units of mg EtOH/dL blood per
mg EtOH/dL air) and varies between 1900 and 2400 in other nations.
The variability in the partition coefficient is due to the fact
that it is highly subject dependent. In other words, each subject
will have a partition coefficient in the 1900 to 2400 range that
depends on his or her physiology. Since knowledge of each subject's
partition coefficient is unavailable in field applications, each
nation assumes a single partition coefficient value that is
globally applied to all measurements. In the U.S., defendants in
DUI cases often use the globally applied partition coefficient as
an argument to impede prosecution.
[0004] Breath measurements have additional limitations. First, the
presence of "mouth alcohol" can falsely elevate the breath alcohol
measurement. This necessitates a 15-minute waiting period prior to
making a measurement in order to ensure that no mouth alcohol is
present. For a similar reason, a 15 minute delay is required for
individuals who are observed to burp or vomit. A delay of 10
minutes or more is often required between breath measurements to
allow the instrument to return to equilibrium with the ambient air
and zero alcohol levels. In addition, the accuracy of breath
alcohol measurements is sensitive to numerous physiological and
environmental factors.
[0005] Multiple government agencies, and society in general, seek
non-invasive alternatives to blood and breath alcohol measurements.
Quantitative spectroscopy offers the potential for a completely
non-invasive alcohol measurement that is not sensitive to the
limitations of the current measurement methodologies. While
non-invasive determination of biological attributes by quantitative
spectroscopy has been found to be highly desirable, it has been
very difficult to accomplish. Attributes of interest include, as
examples, analyte presence, analyte concentration (e.g., alcohol
concentration), direction of change of an analyte concentration,
rate of change of an analyte concentration, disease presence (e.g.,
alcoholism), disease state, and combinations and subsets thereof.
Non-invasive measurements via quantitative spectroscopy are
desirable because they are painless, do not require a fluid draw
from the body, carry little risk of contamination or infection, do
not generate any hazardous waste, and can have short measurement
times.
[0006] Several systems have been proposed for the non-invasive
determination of attributes of biological tissue. These systems
have included technologies incorporating polarimetry, mid-infrared
spectroscopy, Raman spectroscopy, Kromoscopy, fluorescence
spectroscopy, nuclear magnetic resonance spectroscopy,
radio-frequency spectroscopy, ultrasound, transdermal measurements,
photo-acoustic spectroscopy, and near-infrared spectroscopy.
However, these systems have not replaced direct and invasive
measurements.
[0007] As an example, Robinson et al. in U.S. Pat. No. 4,975,581
disclose a method and apparatus for measuring a characteristic of
unknown value in a biological sample using infrared spectroscopy in
conjunction with a multivariate model that is empirically derived
from a set of spectra of biological samples of known characteristic
values. The above-mentioned characteristic is generally the
concentration of an analyte, such as alcohol, but also can be any
chemical or physical property of the sample. The method of Robinson
et al. involves a two-step process that includes both calibration
and prediction steps.
[0008] In the calibration step, the infrared light is coupled to
calibration samples of known characteristic values so that there is
attenuation of at least several wavelengths of the infrared
radiation as a function of the various components and analytes
comprising the sample with known characteristic value. The infrared
light is coupled to the sample by passing the light through the
sample or by reflecting the light off the sample. Absorption of the
infrared light by the sample causes intensity variations of the
light that are a function of the wavelength of the light. The
resulting intensity variations at a minimum of several wavelengths
are measured for the set of calibration samples of known
characteristic values. Original or transformed intensity variations
are then empirically related to the known characteristics of the
calibration samples using multivariate algorithms to obtain a
multivariate calibration model. The model preferably accounts for
subject variability, instrument variability, and environment
variability.
[0009] In the prediction step, the infrared light is coupled to a
sample of unknown characteristic value, and a multivariate
calibration model is applied to the original or transformed
intensity variations of the appropriate wavelengths of light
measured from this unknown sample. The result of the prediction
step is the estimated value of the characteristic of the unknown
sample. The disclosure of Robinson et al. is incorporated herein by
reference.
[0010] A further method of building a calibration model and using
such model for prediction of analytes and/or attributes of tissue
is disclosed in commonly assigned U.S. Pat. No. 6,157,041 to Thomas
et al., entitled "Method and Apparatus for Tailoring Spectrographic
Calibration Models," the disclosure of which is incorporated herein
by reference.
[0011] In U.S. Pat. No. 5,830,112, Robinson describes a general
method of robust sampling of tissue for non-invasive analyte
measurement. The sampling method utilizes a tissue-sampling
accessory that is pathlength optimized by spectral region for
measuring an analyte such as alcohol. The patent discloses several
types of spectrometers for measuring the spectrum of the tissue
from 400 to 2500 nm, including acousto-optical tunable filters,
discrete wavelength spectrometers, filters, grating spectrometers
and FTIR spectrometers. The disclosure of Robinson is incorporated
hereby reference.
[0012] Although there has been substantial work conducted in
attempting to produce commercially viable non-invasive
near-infrared spectroscopy-based systems for determination of
biological attributes, no such device is presently available. It is
believed that prior art systems discussed above have failed for one
or more reasons to fully meet the challenges imposed by the
spectral characteristics of tissue which make the design of a
non-invasive measurement system a formidable task. Thus, there is a
substantial need for a commercially viable device which
incorporates subsystems and methods with sufficient accuracy and
precision to make clinically relevant determinations of biological
attributes in human tissue.
SUMMARY OF THE INVENTION
[0013] The present invention generally relates to a quantitative
spectroscopy system for measuring the presence or concentration of
alcohol, alcohol byproducts, alcohol adducts, or substances of
abuse utilizing non-invasive techniques in combination with
multivariate analysis.
[0014] The present system overcomes the challenges posed by the
spectral characteristics of tissue by incorporating a design that
includes, in some embodiments, five optimized subsystems. The
design contends with the complexities of the tissue spectrum, high
signal-to-noise ratio and photometric accuracy requirements, tissue
sampling errors, calibration maintenance problems, calibration
transfer problems plus a host of other issues. The five subsystems
include an illumination/modulation subsystem, a tissue sampling
subsystem, a data acquisition subsystem, a computing subsystem, and
a calibration subsystem.
[0015] The present invention further includes apparatus and methods
that allow for implementation and integration of each of these
subsystems in order to maximize the net attribute signal-to-noise
ratio. The net attribute signal is the portion of the near-infrared
spectrum that is specific for the attribute of interest because it
is orthogonal to all other sources of spectral variance. The
orthogonal nature of the net attribute signal makes it
perpendicular to the space defined by any interfering species and
as a result, the net attribute signal is uncorrelated to these
sources of variance. The net attribute signal-to-noise ratio is
directly related to the accuracy and precision of the present
invention for non-invasive determination of the attribute by
quantitative near-infrared spectroscopy.
[0016] The present invention can use near-infrared radiation for
analysis. Radiation in the wavelength range of 1.0 to 2.5 microns
(or wavenumber range of 10,000 to 4,000 cm.sup.-1) can be suitable
for making some non-invasive measurements because such radiation
has acceptable specificity for a number of analytes, including
alcohol, along with tissue optical penetration depths of up to 5
millimeters with acceptable absorbance characteristics. In the 1.0
to 2.5 micron spectral region, the large number of optically active
substances that make up the tissue complicate the measurement of
any given substance due to the overlapped nature of their
absorbance spectra. Multivariate analysis techniques can be used to
resolve these overlapped spectra such that accurate measurements of
the substance of interest can be achieved. Multivariate analysis
techniques, however, can require that multivariate calibrations
remain robust over time (calibration maintenance) and be applicable
to multiple instruments (calibration transfer). Other wavelength
regions, such as the visible and infrared, can also be suitable for
the present invention.
[0017] The present invention documents a multidisciplinary approach
to the design of a spectroscopic instrument that incorporates an
understanding of the instrument subsystems, tissue physiology,
multivariate analysis, near-infrared spectroscopy and overall
system operation. Further, the interactions between the subsystems
have been analyzed so that the behavior and requirements for the
entire non-invasive measurement device are well understood and
result in a design for a commercial instrument that will make
non-invasive measurements with sufficient accuracy and precision at
a price and size that is commercially viable.
[0018] The subsystems of the non-invasive monitor are highly
optimized to provide reproducible and, preferably, uniform radiance
of the tissue, low tissue sampling error, depth targeting of the
tissue layers that contain the property of interest, efficient
collection of diffuse reflectance spectra from the tissue, high
optical throughput, high photometric accuracy, large dynamic range,
excellent thermal stability, effective calibration maintenance,
effective calibration transfer, built-in quality control, and
ease-of-use.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 is a schematic depiction of a non-invasive
spectrometer system incorporating the subsystems of the present
invention;
[0020] FIG. 2 is a graphical depiction of the concept of net
attribute signal in a three-component system;
[0021] FIG. 3 is a diagramed view of a system of the present
invention using a means for spatially and angularly homogenizing
emitted radiation;
[0022] FIG. 4 is a schematic of an embodiment of the present
invention incorporating a semiconductor light source with Hadamard
encoding;
[0023] FIG. 5 is a schematic of an embodiment of the present
invention incorporating a semiconductor light source with Hadamard
encoding, where the encoding is performed after the light has
interacted with the sample;
[0024] FIG. 6 is an embodiment of an electronic circuit designed to
monitor and control the temperature of a solid state light
source;
[0025] FIG. 7 is an embodiment of an electronic circuit designed to
control the drive current of a solid state light source including
means for turning the light source on and off;
[0026] FIG. 8 is an embodiment of an electronic circuit designed to
monitor and control the temperature of a solid state light source
including means for altering the desired control temperature;
[0027] FIG. 9 is an embodiment of an electronic circuit designed to
control the drive current of a solid state light source including
means for turning the light source on and off and altering the
desired drive current;
[0028] FIG. 10 is a perspective view of elements of an example
tissue sampling subsystem;
[0029] FIG. 11 is a perspective view of an ergonomic apparatus for
holding the sampling surface and positioning a tissue surface
thereon;
[0030] FIG. 12 is a plan view of the sampling surface of the tissue
sampling subsystem, showing an example arrangement of illumination
and collection optical fibers;
[0031] FIG. 13 is an alternative embodiment of the sampling surface
of the tissue sampling subsystem;
[0032] FIG. 14 is an alternative embodiment of the sampling surface
of the tissue sampling subsystem;
[0033] FIG. 15 is a depicts various aspects of a sampler
orientation;
[0034] FIG. 16 is a diagramed view of a two-channel sampling
subsystem;
[0035] FIG. 17 is a graphical representation showing the benefits
of a two-channel sampling subsystem;
[0036] FIG. 18 is a diagramed view of the interface between the
sampling surface and the tissue when topical interferents are
present on the tissue;
[0037] FIG. 19 is a diagramed view of an alternative positioning
device for the tissue relative to the sampling surface;
[0038] FIG. 20 is a schematic representation of an example data
acquisition subsystem;
[0039] FIG. 21 is a schematic representation that shows various
aspects of an example computing subsystem;
[0040] FIG. 22 is the spectrum of water before and after path
length correction to account for photon propagation through
tissue;
[0041] FIG. 23 is a diagram of a hybrid calibration formation
process;
[0042] FIG. 24 is a schematic representation of a decision process
that combines three topical interferent mitigation strategies;
[0043] FIG. 25 demonstrates the effectiveness of multivariate
calibration outlier metrics for detecting the presence of topical
interferents;
[0044] FIG. 26 shows normalized NIR spectra of 1300 and 3000 K
blackbody radiators over the 100-33000-cm.sup.-1 (100-0.3 microm)
range;
[0045] FIG. 27 shows the measured intensity over time observed for
a demonstrative ceramic blackbody light source;
[0046] FIG. 28 shows the spectral emission profiles of several
demonstrative NIR LED's;
[0047] FIG. 29 is a perspective end view and a detail plan view of
a light pipe suitable for use with the present invention;
[0048] FIG. 30 is an illustration of internal reflection and the
resulting channeling;
[0049] FIG. 31 shows a schematic of the components of an example
embodiment of the present invention;
[0050] FIG. 32 is a schematic of the arrangement of illumination
and collection fibers at the sample interface for an example
embodiment of an optical probe of the present invention;
[0051] FIG. 33 depicts noninvasive tissue spectra acquired using 22
wavelengths;
[0052] FIG. 34 compares noninvasive tissue alcohol concentrations
obtained from the spectra in FIG. 33 to contemporaneous capillary
blood alcohol concentration;
[0053] FIG. 35 is an illustration of the optical combination of
multiple semiconductor light sources.
DETAILED DESCRIPTION OF THE INVENTION
[0054] For the purposes of the present invention, the term "analyte
concentration" generally refers to the concentration of an analyte,
such as alcohol. The term "analyte property" includes analyte
concentration and other properties, such as the presence or absence
of the analyte or the direction or rate of change of the analyte
concentration, or a biometric, which can be measured in conjunction
with or instead of the analyte concentration. While the disclosure
generally references alcohol as the "analyte" of interest, other
analytes, including but not limited to substances of abuse, alcohol
biomarkers, and alcohol byproducts, can also benefit from the
present invention. The term "alcohol" is used as an example analyte
of interest; the term is intended to include ethanol, methanol,
ethyl glycol or any other chemical commonly referred to as alcohol.
For the purposes of this invention, the term "alcohol byproducts"
includes the adducts and byproducts of the metabolism of alcohol by
the body including, but not limited to, acetone, acetaldehyde, and
acetic acid. The term "alcohol biomarkers" includes, but is not
limited to, Gamma Glutamyl Transferase (GGT), Aspartate Amino
Transferase (AST), Alanine Amino Transferase (ALT), Mean
Corpuscular Volume (MCV), Carbohydrate-Deficient Transferrin (CDT),
Ethyl Glucuronide (EtG), Ethyl Sulfate (EtS), and Phosphatidyl
Ethanol (PEth). The term "substances of abuse" refers to, but is
not limited to, THC (Tetrahydrocannabinol or marijuana), cocaine,
M-AMP (methamphetamine), OPI (morphine and heroin), OxyContin,
Oxycodone, and PCP (phencyclidine). The term "biometric" refers to
an analyte or biological characteristic that can be used to
identify or verify the identity of a specific person or subject.
The present invention addresses the need for analyte measurements
of samples utilizing spectroscopy where the term "sample" generally
refers to biological tissue. The term "subject" generally refers to
a person from whom a sample measurement was acquired.
[0055] The terms "solid state light source" or "semiconductor light
source" refer to all sources of light, whether spectrally narrow
(e.g. a laser) or broad (e.g. an LED) that are based upon
semiconductors which include, but are not limited to, light
emitting diodes (LED's), vertical cavity surface emitting lasers
(VCSEL's), horizontal cavity surface emitting lasers (HCSEL's),
quantum cascade lasers, quantum dot lasers, diode lasers, or other
semiconductor diodes or lasers. Furthermore, plasma light sources
and organic LED's, while not strictly based on semiconductors, are
also contemplated in the embodiments of the present invention and
are thus included under the solid state light source and
semiconductor light source definitions for the purposes of this
disclosure.
[0056] For the purposes of this invention the term "dispersive
spectrometer" indicates a spectrometer based upon any device,
component, or group of components that spatially separate one or
more wavelengths of light from other wavelengths. Examples include,
but are not limited to, spectrometers that use one or more
diffraction gratings, prisms, holographic gratings. For the
purposes of this invention the term "interferometric/modulating
spectrometer" indicates a class of spectrometers based upon the
optical modulation of different wavelengths of light to different
frequencies in time or selectively transmits or reflects certain
wavelengths of light based upon the properties of light
interference. Examples include, but are not limited to, Fourier
transform interferometers, Sagnac interferometers, mock
interferometers, Michelson interferometers, one or more etalons, or
acousto-optical tunable filters (AOTF's). One skilled in the art
recognizes that spectrometers based on combinations of dispersive
and interferometric/modulating properties, such as those based on
lamellar gratings, are also contemplated with respect to the
present invention.
[0057] The invention makes use of "signals", described in some of
the examples as absorbance or other spectroscopic measurements.
Signals can comprise any measurement obtained concerning the
spectroscopic measurement of a sample or change in a sample, e.g.,
absorbance, reflectance, intensity of light returned, fluorescence,
transmission, Raman spectra, or various combinations of
measurements, at one or more wavelengths. Some embodiments make use
of one or more models, where such a model can be anything that
relates a signal to the desired property. Some examples of models
include those derived from multivariate analysis methods, such as
partial least squares regression (PLS), linear regression, multiple
linear regression (MLR), classical least squares regression (CLS),
neural networks, discriminant analysis, principal components
analysis (PCA), principal components regression (PCR), discriminant
analysis, neural networks, cluster analysis, and K-nearest
neighbors. Single or multi-wavelength models based on the
Beer-Lambert law are special cases of classical least squares and
are thus included in the term multivariate analysis for the
purposes of the present invention.
[0058] The following detailed description should be read with
reference to the drawings. The drawings, which are not necessarily
to scale, depict illustrative embodiments that are not intended to
limit the scope of the invention. For the purposes of the
application, the term "about" applies to all numeric values,
whether or not explicitly indicated. The term "about" generally
refers to a range of numbers that one of skill in the art would
consider equivalent to the recited value (i.e., having the same
function or result). In some instances, the term "about" can
include numbers that are rounded to the nearest significant
figure.
[0059] Spectroscopic measurement systems typically require some
means for resolving and measuring different wavelengths of light in
order to obtain a spectrum. Some common approaches achieve the
desired spectrum include dispersive (e.g. grating and prism based)
spectrometers and interferometric (e.g. Michelson, Sagnac, or other
interferometer) spectrometers. Noninvasive measurement systems that
incorporate such approaches are often limited by the expensive
nature of dispersive and interferometric devices as well as their
inherent size, fragility, and sensitivity to environmental effects.
The present invention can provide an alternative approach for
resolving and recording the intensities of different wavelengths
using solid state light sources such as light emitting diodes
(LED's), vertical cavity surface emitting lasers (VCSEL's),
horizontal cavity surface emitting lasers (VCSEL's), diode lasers,
quantum cascade lasers, or other solid state light sources.
[0060] Referring now to FIG. 1, a non-invasive monitor that is able
to achieve acceptable levels of accuracy and precision for analyte
property measurements is depicted in schematic view. The overall
systems of the present invention can be viewed for discussion
purposes as comprising five subsystems; those skilled in the art
will appreciate other subdivisions of the functionality disclosed.
The subsystems include an illumination/modulation subsystem 100, a
tissue sampling subsystem 200, a data acquisition subsystem 300, a
processing subsystem 400, and a calibration subsystem (not
shown).
[0061] The subsystems can be designed and integrated in order to
achieve a desirable net attribute signal-to-noise ratio. The net
attribute signal is the portion of the near-infrared spectrum that
is specific for the attribute of interest because it is orthogonal
to other sources of spectral variance.
[0062] FIG. 2 is a graphical representation of the net attribute
signal in a three dimensional system. The net attribute
signal-to-noise ratio is directly related to the accuracy and
precision of the non-invasive attribute determination by
quantitative near-infrared spectroscopy with the present
invention.
[0063] The subsystems provide reproducible and preferably spatially
uniform radiance of the tissue, low tissue sampling error, depth
targeting of appropriate layers of the tissue, efficient collection
of diffuse reflectance spectra from the tissue, high optical
throughput, high photometric accuracy, large dynamic range,
excellent thermal stability, effective calibration maintenance,
effective calibration transfer, built-in quality control and
ease-of-use. Each of the subsystems is discussed below in more
detail.
Illumination/Modulation Subsystem (100)
[0064] The illumination/modulation subsystem 100 generates the
light used to interrogate the sample (e.g. skin tissue of a human).
In classical spectroscopy using dispersive or interferometric
spectrometers, the spectrum of a polychromatic light source (or
sample of interest) is measured either by dispersing the different
wavelengths of light spatially (e.g. using a prism or a diffraction
grating) or by modulating different wavelengths of light to
different frequencies (e.g. using a Michelson interferometer). In
these cases, a spectrometer (a subsystem distinct from the light
source) is required to perform the function of "encoding" different
wavelengths either spatially or in time such that each can be
measured substantially independently of other wavelengths. While
dispersive and interferometric spectrometers are known in the art
and can adequately serve their function in some environments and
applications, they can be limited by their cost, size, fragility,
and complexity in other applications and environments.
[0065] An advantage of solid-state light sources incorporated in
the systems disclosed in the present invention is that they can be
modulated in intensity. Thus, multiple light sources that emit
different wavelengths of light can be used with each light source
modulated at a different frequency. The independently modulated
light sources can be optically combined into a single beam and
introduced to the sample. A portion of the light can be collected
from the sample and measured by a single photodetector. The result
is the effective combination of the light source and the
spectrometer into a single illumination/modulation subsystem that
can offer significant benefits in size, cost, energy consumption,
and overall system stability since the spectrometer, as an
independent subsystem, is eliminated from the measurement
system.
[0066] Several parameters of systems for measuring analyte
properties incorporating solid state light sources must be
considered including, but not limited to, the number of solid-state
light sources required to perform the desired measurement, the
emission profile of the light sources (e.g. spectral width,
intensity), light source stability and control, and their optical
combination. As each light source is a discrete element, it can be
advantageous to combine the output of multiple light sources into a
single beam such that they are consistently introduced and
collected from the sample.
[0067] Furthermore, the modulation scheme for the light sources
must also be considered as some types of sources can be amenable to
sinusoidal modulations in intensity where others can be amenable to
being switched on and off or square wave modulated. In the case of
sinusoidal modulation, multiple light sources can be modulated at
different frequencies based on the electronics design of the
system. The light emitted by the multiple sources can be optically
combined, for example using a light pipe or other homogenizer,
introduced and collected from the sample of interest, and then
measured by a single detector. The resulting signal can be
converted into an intensity versus wavelength spectrum via a
Fourier, or similar, transform.
[0068] Alternatively, some light sources are switched between the
on and off state or square wave modulated which are amenable to a
Hadamard transform approach. However, in some embodiments, rather
than a traditional Hadamard mask that blocks or passes different
wavelengths at different times during a measurement, the Hadamard
scheme can be implemented in electronics as solid state light
sources can be cycled at high frequencies. A Hadamard or similar
transform can be used to determine the intensity versus wavelength
spectrum.
[0069] Another advantage of solid state light sources is that many
types (e.g. VCSELs) emit a narrow range of wavelengths (which in
part determines the effective resolution of the measurement).
Consequently, in some example embodiments, shaping or narrowing the
emission profile of light sources with optical filters or other
approaches is not required as they are already sufficiently narrow.
This can be advantageous due to decreased system complexity and
cost. Furthermore, the emission wavelengths of some solid state
light sources, such as VCSEL's, are tunable over a range of
wavelengths via either the supplied drive current, drive voltage,
or by changing the temperature of the light source. The advantage
of this approach is that if a given measurement requires a specific
number of wavelengths, the system can achieve the requirement with
fewer discrete light sources by tuning them over their feasible
ranges. For example, if measurement of a noninvasive property
required 20 wavelengths, 10 discrete VCSEL's might be used with
each of the 10 being tuned to 2 different wavelengths during the
course of a measurement. In this type of scheme, a Fourier or
Hadamard approach remains appropriate by changing the modulation
frequency for each tuning point of a light source or by combining
the modulation scheme with a scanning scheme.
[0070] It is important to note that the present invention also
envisions several embodiments of blackbody light sources rather
than solid-state light sources. In these embodiments, the broad
blackbody source is converted to multiple, narrow light sources
using optical filters such as, but not limited to, linearly
variable filters (LVF's), dielectric stacks, distributed Bragg
gratings, photonic crystal lattice filters, polymer films,
absorption filters, reflection filters, etelons, dispersive
elements such as prisms and gratings, and quantum dot filters. The
resulting multiple bands of wavelengths can be modulated by a
Fourier scheme or Hadamard mask. Similar to the solid-state
concepts, the spectrometer system is combined with the light source
which can offer substantial benefits in terms of size, cost, and
the robustness of the system.
[0071] In other embodiments, a dispersive element such as a grating
or prism is used to spatially separate the wavelengths of light
from a broad band source (either a blackbody, LED, or other broad
emitting light source). The dispersive element separates the
different wavelengths which can be independently modulated at their
locations on a focal plane using a Hadamard mask or mechanical
chopper (e.g. for a Fourier scheme). Similar to the embodiments
previously described, the resulting light can be homogenized and
introduced to the optical probe. FIGS. 4 and 5 show schematics of
embodiments of the present invention that incorporate a blackbody
light source with Hadamard encoding.
[0072] In mechanically modulated embodiments incorporating a
Hadamard mask or mechanical chopper, in some cases it can be
advantageous to perform the modulating step after the light has
been collected from the sample by the optical probe (200). FIG. 5
shows a schematic of an embodiment of such a system.
[0073] Analyte properties can be measured at a variety of
wavelengths spanning the ultraviolet and infrared regions of the
electromagnetic spectrum. For in vivo measurements in skin, such as
alcohol or substances of abuse, the near infrared (NIR) region of
1,000 nm to 2,500 nm region can be important due to the sensitivity
and specificity of the spectroscopic signals for the analyte of
interest as well as other chemical species (e.g. water) that are
present in human skin. Furthermore, the absorptivities of the
analytes are low enough that the near infrared light can penetrate
a few millimeters into the skin where the analytes of interest
reside. The 2,000 nm to 2,500 nm wavelength range can be of
particular utility as it contains combination bands rather than the
weaker, less distinct overtones encountered in the 1,000 to 2,000
nm portion of the NIR.
[0074] In addition to the commonly available LEDs, VCSELs, diode
lasers in the visible region of the spectrum, there are solid state
light sources available with emission wavelengths throughout the
NIR region (1,000 to 2,500 nm). These light sources are suitable
for the analyte and biometric property measurement systems of the
present invention. Some examples of available NIR solid state light
sources that are VCSELs produced by Vertilas GmbH, and the VCSEL's,
quantum cascade lasers, laser diodes available from Laser
Components GmbH, or lasers and diodes available from Roithner
Laser, Epitex, Dora Texas Corporation, Microsensor Tech, SciTech
Instruments, Laser 2000, Redwave Labs, and Deep Red Tech. These
examples are included for demonstrative purposes and are not
intended to be limiting of the types of solid state light sources
suitable for use with the present invention.
Measurement Resolution and Resolution Enhancement
[0075] In a dispersive spectrometer the effective resolution of a
spectroscopic measurement is often determined by the width of an
aperture in the system. The resolution limiting aperture is often
the width of the entrance slit. At the focal plane where light
within the spectrometer is detected, multiple images of the slit
are formed, with different wavelengths located at different spatial
locations on the focal plane. Thus, the ability to detect one
wavelength independent of its neighbors is dependent on the width
of the slit. Narrower widths allow better resolution between
wavelengths at the expense of the amount of light that can be
passed through the spectrometer. Consequently, resolution and
signal to noise ratio generally trade against each other.
Interferometric spectrometers have a similar trade between
resolution and signal to noise ratio. In the case of a Michelson
interferometer the resolution of the spectrum is in part determined
by the distance over which a moving mirror is translated with
longer distances resulting in greater resolution. The consequence
is that the greater the distance, the more time is required to
complete a scan.
[0076] In the case of the measurement systems of the present
invention, the resolution of the spectrum is determined by the
spectral width of each of the discrete light sources (whether a
different light source, one tuned to multiple wavelengths, or a
combination thereof). For measurements of analyte properties
requiring high resolution, a VCSEL or other suitable solid state
laser can be used. The widths of the laser's emission can be very
narrow, which translates into high resolution. In measurement
applications where moderate to low resolution are required, LED's
can be suitable as they typically have wider emission profiles (the
output intensity is distributed across a wider range of
wavelengths) than solid state laser alternatives.
[0077] The effective resolution of light sources can be enhanced
through the use, or combination of, different types of optical
filters. The spectral width of a light source can be narrowed or
attenuated using one or more optical filters in order to achieve
higher resolution (e.g. a tighter range of emitted wavelengths).
Examples of optical filters that are contemplated in embodiments of
the present invention include, but are not limited to: linearly
variable filters (LVF's), dielectric stacks, distributed Bragg
gratings, photonic crystal lattice filters, polymer films,
absorption filters, reflection filters, etelons, dispersive
elements such as prisms and gratings, and quantum dot filters.
[0078] Another means for improving the resolution of measurements
obtained from embodiments of the present invention is
deconvolution. Deconvolution, and other similar approaches, can be
used to isolate the signal difference that is present between two
or more overlapping broad light sources. For example, two light
sources with partially overlapping emission profiles can be
incorporated into a measurement system. A measurement can be
acquired from a sample and a spectrum generated (via a Hadamard,
Fourier transform, or other suitable transform). With knowledge of
the emission profiles of the light sources, the profiles can be
deconvolved from the spectrum in order to enhance the resolution of
the spectrum.
Stabilization and Control of Light Source Wavelength and
Intensity
[0079] The peak emission wavelength of solid state light sources,
particularly lasers, can be influenced by changing the thermal
state or electrical properties (e.g. drive current or voltage) of
the light source. In the case of semi conductor lasers, changing
the thermal state and electrical properties alters the optical
properties or physical dimensions of the lattice structure of the
semiconductor. The result is a change in the cavity spacing within
the device, which alters the peak wavelength emitted. Since solid
state light sources exhibit these effects, when they are used in
spectroscopic measurement systems the stability of the peak
wavelength of emission and its associated intensity can be
important parameters. Consequently, during a measurement control of
both the thermal state and electrical properties of each light
source can be advantageous in terms of overall system robustness
and performance. Furthermore, the change in optical properties
caused by thermal state and electrical conditions can be leveraged
to allow a single light source to be tuned to multiple peak
wavelength locations. This can result in analyte property
measurement systems that can measure more wavelength locations than
the number of discrete light sources which can reduce system cost
and complexity.
[0080] Temperature stabilization can be achieved using multiple
approaches. In some embodiments, a light source or light sources
can be stabilized by raising the temperature above (or cooling
below) ambient conditions with no additional control of the
temperature. In other embodiments, the light source or light
sources can be actively controlled to a set temperature (either
cooled or heated) using a control loop. A diagram of a temperature
control loop circuit suitable for the present invention is shown in
FIG. 6.
[0081] The electrical properties of light sources also influence
the emission profile (e.g. wavelength locations of emission) of
solid state light sources. It can be advantageous to stabilize the
current and/or voltage supplied to the light source or light
sources. For example, the peak emission of VCSELs depends on drive
current. For embodiments where the stability of the peak wavelength
is important, the stability of the drive current becomes an
important figure of merit. In such cases, an electronic circuit can
be designed to supply a stable drive current to the VCSEL. The
complexity and cost of the circuit can depend on the required
stability of the drive current. FIG. 7 shows a current drive
circuit suitable for use with the present invention. One skilled in
the art recognizes that alternative embodiments of current control
circuits are known in the art and can also be suitable for the
present invention. Furthermore, some solid state light sources
require control of the drive voltage, rather than drive current;
one skilled in the art recognizes that electronics circuits
designed to control voltage rather than current are readily
available.
[0082] In some embodiments, a single solid state light source, such
as a VCSEL, is tuned to multiple wavelengths during the course of a
measurement. In order to achieve the tuning of the light sources,
the circuits shown in FIGS. 6 and 7 can be modified to include the
control of the temperature set point and current, respectively.
FIGS. 8 and 9 depict embodiments of temperature and current control
circuits, respectively, that allow tuning of the emission
wavelength. In some embodiments, either tuning temperature or drive
current/voltage can be sufficient to realize the desired tuning of
the peak emission wavelength. In other embodiments, control of both
the temperature and drive current/voltage can be required to
achieve the desired tuning range.
[0083] Furthermore, optical means for measuring and stabilizing the
peak emission wavelength can also be incorporated into the systems
described in connection with the present invention. A Fabry-Perot
etalon can be used to provide a relative wavelength standard. The
free spectral range and finesse of the etalon can be specified to
provide an optical passband that allows active measurement and
control of the VCSEL peak wavelength. An example embodiment of this
etalon uses a thermally stabilized, flat fused-silica plate with
partially mirrored surfaces. For systems where each VCSEL is
required to provide multiple wavelengths, the free spectral range
of the etalon can be chosen such that its transmission peaks
coincide with the desired wavelength spacing for tuning. One
skilled in the art will recognize that there are many optical
configurations and electronic control circuits that are viable for
this application. One example control circuit is showing in FIG. 9.
An alternate wavelength encoding scheme uses a dispersive grating
and a secondary array detector to encode the VCSEL wavelength into
a spatial location on the array. For either the dispersive or the
etalon based schemes, a secondary optical detector that has less
stringent performance requirements than the main optical detector
can be used. Active control can reduce the stability requirements
of the VCSEL temperature and current control circuits by allowing
real time correction for any drift.
[0084] Light homogenizers such as optical diffusers, light pipes,
and other scramblers can be incorporated into some embodiments of
the illumination/modulation subsystem 100 in order to provide
reproducible and, preferably, uniform radiance at the input of the
tissue sampling subsystem 200. Uniform radiance can ensure good
photometric accuracy and even illumination of the tissue. Uniform
radiance can also reduce errors associated with manufacturing
differences between light sources. Uniform radiance can be utilized
in the present invention for achieving accurate and precise
measurements. See, e.g., U.S. Pat. No. 6,684,099, incorporated
herein by reference.
[0085] A ground glass plate is an example of an optical diffuser.
The ground surface of the plate effectively scrambles the angle of
the radiation emanating from the light source and its transfer
optics. A light pipe can be used to homogenize the intensity of the
radiation such that it is spatially uniform at the output of the
light pipe. In addition, light pipes with a double bend will
scramble the angles of the radiation. For creation of uniform
spatial intensity and angular distribution, the cross section of
the light pipe should not be circular. Square, hexagonal and
octagonal cross sections are effective scrambling geometries. The
output of the light pipe can directly couple to the input of the
tissue sampler or can be used in conjunction with additional
transfer optics before the light is sent to the tissue sampler.
See, e.g., U.S. patent application Ser. No. 09/832,586,
"Illumination Device and Method for Spectroscopic Analysis,"
incorporated herein by reference.
Sampling Subsystem 200
[0086] FIG. 1 indicates that the orientation of the tissue sampling
subsystem 200 is between the illumination/modulation (100) and data
acquisition (300) subsystems. Referring to FIG. 1, the tissue
sampling subsystem 200 introduces radiation generated by the
illumination/modulation subsystem 100 into the tissue of the
subject, collects a portion of the radiation that is not absorbed
by the tissue and sends that radiation to optical detector in the
data acquisition subsystem 300 for measurement. FIGS. 10 through 20
depict elements of an example tissue sampling subsystem 200.
Referring to FIG. 10, the tissue sampling subsystem 200 has an
optical input 202, a sampling surface 204 which forms a tissue
interface 206 that interrogates the tissue and an optical output
207. The subsystem further includes an ergonomic apparatus 210,
depicted in FIG. 11, which holds the sampling surface 204 and
positions the tissue at the interface 206. In an example subsystem,
a device that thermostats the tissue interface is included and, in
some embodiments, an apparatus that repositions the tissue on the
tissue interface in a repetitive fashion is included. In other
embodiments, an index matching fluid can be used to improve the
optical interface between the tissue and sampling surface. The
improved interface can reduce error and increase the efficiency,
thereby improving the net attribute signal. See, e.g. U.S. Pat.
Nos. 6,622,032, 6,152,876, 5,823,951, and 5,655,530, incorporated
herein by reference.
[0087] The optical input 202 of the tissue sampling subsystem 200
receives radiation from the illumination/modulation subsystem 100
(e.g., light exiting a light pipe) and transfers that radiation to
the tissue interface 206. As an example, the optical input can
comprise a bundle of optical fibers that are arranged in a
geometric pattern that collects an appropriate amount of light from
the illumination/modulation subsystem. FIG. 12 depicts one example
arrangement. The plan view depicts the ends of the input and output
fibers in a geometry at the sampling surface including six clusters
208 arranged in a circular pattern. Each cluster includes four
central output fibers 212 which collect diffusely reflected light
from the tissue. Around each grouping of four central output fibers
212 is a cylinder of material 215 which ensures about a 100 .mu.m
gap between the edges of the central output fibers 212 and the
inner ring of input fibers 214. The 100 .mu.m gap can be important
to measuring ethanol in the dermis. As shown in FIG. 12, two
concentric rings of input fibers 214 are arranged around the
cylinder of material 215. As shown in one example embodiment, 32
input fibers surround four output fibers.
[0088] FIG. 13 demonstrates an alternative to cluster geometries
for the sampling subsystem. In this embodiment, the illumination
and collection fiber optics are arranged in a linear geometry. Each
row can be either for illumination or light collection and can be
of any length suitable to achieve sufficient signal to noise. In
addition, the number of rows can be 2 or more in order to alter the
physical area covered by the sampling subsystem. The total number
of potential illumination fibers is dependent on the physical size
of emissive area of the light source and the diameter of each
fiber. Multiple light sources can be used to increase the number of
illumination fibers. The number of collection fibers depends upon
the area of the interface to the interferometer subsystem. If the
number of collection fibers results in an area larger than the
interferometer subsystem interface allows, a light pipe or other
homogenizer followed by an aperture can be used to reduce the size
of the output area of the sampling subsystem. The purpose of the
light pipe or other homogenizer is to ensure that each collection
fiber contributes substantially equally to the light that passes
through the aperture.
[0089] In some embodiments the sampling subsystem of the present
invention, the portion of the optical probe that interacts with the
sample can be comprised of a stack of two or more linear ribbons of
optical fibers. These arrangements allow the size and shape of the
optical probe interface to be designed appropriately for the sample
and measurement location (e.g. hand, finger) of interest. FIG. 14
shows an example embodiment of a sampling subsystem based on a
linear stack off ribbons. Additional details regarding suitable
embodiments for use in the present invention can be found in
co-pending U.S. application Ser. Nos. 12/185,217 and 12/185,224,
each of which is incorporated herein by reference.
[0090] The sampling subsystems can also use one or more channels,
where a channel refers to a specific orientation of the
illumination and collection fibers. An orientation is comprised of
the angle of the illumination fiber or fibers, the angle of the
collection fiber or fibers, the numerical aperture of the
illumination fiber or fibers, the numerical aperture of the
collection fiber or fibers, and the separation distance between the
illumination and collection fiber or fibers. FIG. 15 is a diagram
of parameters that form an orientation. Multiple channels can be
used in conjunction, either simultaneously or serially, to improve
the accuracy of the noninvasive measurements. FIG. 16 is a diagram
of a two channel sampling subsystem. In this example, the two
channels are measuring the same tissue structure. Therefore each
channel provides a measurement of the same tissue from a different
perspective. The second perspective helps to provide additional
spectroscopic information that helps to decouple the signals due to
scattering and absorption. Referring to FIG. 16, the group of
fibers (1 source, 1 receiver #1, and 1 receiver #2 in this example)
can be replicated 1 to N times in order to increase the sampler
area and improve optical efficiency. Each of the fibers can have a
different numerical aperture and angle (.theta.). The distances
between fibers, X and Y, determine the source-receiver separation.
Furthermore, an additional source channel can be added that creates
a 4-channel sampling subsystem. One skilled in the art recognizes
the large number of possible variants on the number and
relationship between channels.
[0091] FIG. 17 is a bar chart of example of the benefits of a
multiple channel sampler that was used for noninvasive glucose
measurements. It is clear from the figure that the combination of
the two channels provides superior measurement accuracy when
compared to either channel individually. While this example uses
two channels, additional channels can provide additional
information that can further improve the measurement.
[0092] Another aspect of a multiple channel sampling subsystem is
the ability to improve detection and mitigation of topical
interferents, such as sweat or lotion, present on the sample. FIG.
18 is a diagram of a multiple channel sampling subsystem in the
presence of a topical interferent. The figure shows the sampling
subsystem at the tissue interface, a layer of topical interferent,
and the tissue. In this example the contribution to each channel's
measurement due to the topical interferent is identical. The path
through interferent is similar for both channels, while path
through tissue is different. This allows the potential to decouple
the common topical interferent signal present in both channels from
the tissue signal that will be different for the two channels.
[0093] The clustered input and output fibers are mounted into a
cluster ferrule that is mounted into a sampling head 216. The
sampling head 216 includes the sampling surface 204 that is
polished flat to allow formation of a good tissue interface.
Likewise, the input fibers are clustered into a ferrule 218
connected at the input ends to interface with the
illumination/modulation subsystem 100. The output ends of the
output fibers are clustered into a ferrule 220 for interface with
the data acquisition subsystem 300.
[0094] The optical input can use a combination of light pipes,
refractive and/or reflective optics to transfer input light to the
tissue interface. It can be important that the input optics of the
tissue sampling subsystem collect sufficient light from the
illumination/modulation subsystem 100 in order to achieve an
acceptable net attribute signal.
[0095] The tissue interface irradiates the tissue in a manner that
targets the compartments of the tissue pertinent to the attribute
of interest, and can discriminate against light that does not
travel a significant distance through those compartments. As an
example, a 100-.mu.m gap discriminates against light that contains
little attribute information. In addition, the tissue interface can
average over a certain area of the tissue to reduce errors due to
the heterogeneous nature of the tissue. The tissue sampling
interface can reject specular and short pathlength rays and it can
collect the portion of the light that travels the desired
pathlength through the tissue with high efficiency in order to
maximize the net attribute signal of the system. The tissue
sampling interface can employ optical fibers to channel the light
from the input to the tissue in a predetermined geometry as
discussed above. The optical fibers can be arranged in pattern that
targets certain layers of the tissue that contain good attribute
information.
[0096] The spacing, angle, numerical aperture, and placement of the
input and output fibers can be arranged in a manner to achieve
effective depth targeting. In addition to the use of optical
fibers, the tissue sampling interface can use a non-fiber based
arrangement that places a pattern of input and output areas on the
surface of the tissue. Proper masking of the non-fiber based tissue
sampling interface ensures that the input light travels a minimum
distance in the tissue and contains valid attribute information.
Finally, the tissue sampling interface can be thermostatted to
control the temperature of the tissue in a predetermined fashion.
The temperature of the tissue sampling interface can be set such
that the invention reduces prediction errors due to temperature
variation. Further, reference errors are reduced when building a
calibration model. These methods are disclosed in U.S. patent
application Ser. No. 09/343,800, entitled "Method and Apparatus for
Non-Invasive Blood Analyte Measurement with Fluid Compartment
Equilibration," which is incorporated herein by reference.
[0097] The tissue sampling subsystem can employ an ergonomic
apparatus or cradle 210 that positions the tissue over the sampling
interface 206 in a reproducible manner. An example ergonomic
apparatus 210 is depicted in FIG. 11. In the case of sampling the
underside of the forearm, an ergonomic cradle design is essential
to ensure good contact with the sampling interface. The ergonomic
cradle 210 includes a base 221 having an opening 223 therethrough.
The opening is sized for receiving the sample head 216 therein to
position the sampling surface 204 generally coplanar with an upper
surface 225 of the base 221. The ergonomic cradle 210 references
the elbow and upper arm of the subject via a bracket 222 in
conjunction with a float-to-fit handgrip 224 to accurately position
the forearm on the tissue sampling interface. Careful attention
must be given to the ergonomics of the tissue sampling interface or
significant sampling error can result.
[0098] The example ergonomic cradle 210 is designed such that the
forearm of the subject is reliably located over the sampling head
216. The bracket 222 forms an elbow rest that sets the proper angle
between the upper arm and the sampling head 216, and also serves as
a registration point for the arm. The adjustable hand rest 224 is
designed to hold the fingers in a relaxed manner. The hand rest
position is adjusted for each subject to accommodate different
forearm lengths. In some embodiments, a lifting mechanism is
included which raises and lowers the cradle periodically during
sampling to break and reform the tissue interface. Reformation of
the interface facilitates reduction of sampling errors due to the
rough nature and heterogeneity of the skin. Alternate sites, for
example fingertips, can also be accommodated using variations of
the systems described herein.
[0099] An alternative to the ergonomic cradle is diagramed in FIG.
19. Instead of a cradle located on the measurement system, the
positioning device is located on the tissue. The positioning device
can either be reusable or disposable and can be adhered to the
tissue with medical adhesive. The positioning device can also
include an optically transparent film or other material that
prevents physical contact with the sampling subsystem while
preserving the desired optical characteristics of the measurement.
The positioning device interfaces to the sampling subsystem in a
pre-determined manner, such as alignment pins, in order to
reproducibly locate the tissue to the sampling subsystem. The
positioning device also prevents movement of the tissue relative to
the sampling subsystem during the measurement process.
[0100] The output of the tissue sampling subsystem 200 transfers
the portion of the light not absorbed by the tissue that has
traveled an acceptable path through the tissue to the optical
detector in the data acquisition subsystem 300. The output of the
tissue sampling subsystem 200 can use any combination of refractive
and/or reflective optics to focus the output light onto the optical
detector. In some embodiments, the collected light is homogenized
(see U.S. Pat. No. 6,684,099, Apparatus and Methods for Reducing
Spectral Complexity in Optical Sampling, incorporated herein by
reference) in order to mitigate for spatial and angular effects
that might be sample dependent (see FIG. 3).
[0101] As an example application, the non-invasive measurement of
alcohol in humans places extreme requirements on the performance of
the instrumentation due to the small size of the alcohol absorption
spectrum relative to the water absorption of the body. In addition,
interferences due to absorption of other spectroscopically active
compounds such as collagen, lipids, protein, etc. reduce the useful
portions of the alcohol absorption spectrum, yielding a net
attribute signal that is small. To first order approximation, 1
mg/dl of alcohol concentration change is equivalent to 7 Au of
spectral variance for the effective pathlength light travels
through tissue using the present invention. Therefore, in order to
measure alcohol non-invasively with clinically acceptable accuracy,
the spectrometer portion of the non-invasive alcohol monitor must
have a large signal-to-noise ratio (SNR) and excellent photometric
accuracy.
Data Acquisition Subsystem 300
[0102] The data acquisition subsystem 300 converts the optical
signal from the sampling subsystem into a digital representation.
FIG. 20 is a schematic representation of the data acquisition
subsystem. An important aspect of the present invention is that,
similar to an interferometric spectrometer, only a single element
detector is required to measure all desired wavelengths. Array
detectors and their supporting electronics are a significant
drawback due to their expensive nature.
[0103] The optical detector converts the incident light into an
electrical signal as a function of time. Examples of detectors that
are sensitive in the spectral range of 1.0 to 2.5 microm include
InGaAs, InAs, InSb, Ge, PbS, and PbSe. An example embodiment of the
present invention can utilize a 1-mm, thermo-electrically cooled,
extended range InGaAs detector that is sensitive to light in the
1.0 to 2.5 microm range. The 2.5 microm, extended range InGaAs
detector has low Johnson noise and, as a result, allows Shot noise
limited performance for the photon flux emanating from the tissue
sampling subsystem. The extended InGaAs detector has peak
sensitivity in the 2.0 to 2.5 microm spectral region where three
very important alcohol absorption features are located. In
comparison with the liquid nitrogen cooled InSb detector, the
thermo-electrically cooled, extended range InGaAs can be more
practical for a commercial product. Also, this detector exhibits
over 120 dbc of linearity in the 1.0 to 2.5 microm spectral region.
Alternative detectors can be suitable if the alcohol measurement
system utilizes alternative wavelength regions. For example, a
silicon detector can be suitable if the wavelength range of
interest were within the 300-1100 nm range.
[0104] Any photodetector can be used with the present invention as
long as the given photodetector satisfies basic sensitivity, noise
and speed requirements. A suitable photodetector can have a shunt
resistance greater than 6000 ohms, a terminal capacitance less than
6 nano farads and a minimum photosensitivity of 0.15 amps per watt
over the 1.0 to 2.5 micron spectral region. In addition, the
photodetector can have a cut-off frequency greater than or equal to
1000 hertz. The shunt resistance of the photodetector defines the
Johnson or thermal noise of the detector. The Johnson noise of the
detector must be low relative to the photon flux at the detector to
ensure Shot noise limited performance by the detector. The terminal
capacitance governs the cut-off frequency of the photodetector and
may also be a factor in the high frequency noise gain of the
photodetector amplifier. The photo sensitivity is an important
factor in the conversion of light to an electrical current and
directly impacts the signal portion of the SNR equation.
[0105] The remainder of the data acquisition subsystem 300
amplifies and filters the electrical signal from the detector and
then converts the resulting analog electrical signal to its digital
representation with an analog to digital converter, digital
filtering, and re-sampling of the digital signal from equal time
spacing to equal position spacing. The analog electronics and ADC
must support the high SNR and linearity inherent in the signal. To
preserve the SNR and linearity of the signal, the data acquisition
subsystem 300 can support at least 100 dbc of SNR plus distortion.
The data acquisition subsystem 300 can produce a digitized
representation of the signal. In some embodiments, a 24-bit
delta-sigma ADC can be operated at 96 or 192 kilohertz. If system
performance requirements permit, alternate analog to digital
converters can be used in which the sample acquisition is
synchronized with the light source modulation rather than captured
at equal time intervals. The digitized signal can be passed to an
embedded computer subsystem 600 for further processing, as
discussed below.
[0106] Further, the data acquisition subsystem 300 can utilize a
constant time sampling, dual channel, delta-sigma analog-to-digital
converter (ADC) to support the SNR and photometric accuracy
requirements of the present non-invasive glucose measurement. In
some embodiments, the delta-sigma ADC utilized supports sampling
rates of over 100 kHz per channel, has a dynamic range in excess of
117 dbc and has total harmonic distortion less than -105 dbc. In a
system that has only one channel of signal to digitize (instead of
the two more common in delta-sigma ADC's), the signal can be passed
into both inputs of the ADC and averaged following digitization.
This operation can help to reduce any uncorrelated noise introduced
by the ADC.
[0107] The constant time sampling data acquisition subsystem 300
has several distinct advantages over other methods of digitizing
signals. These advantages include greater dynamic range, lower
noise, reduced spectral artifacts; detector noise limited operation
and simpler and less expensive analog electronics. In addition, the
constant time sampling technique allows digital compensation for
frequency response distortions introduced by the analog electronics
prior to the ADC. This includes non-linear phase error in
amplification and filtering circuits as well as the non-ideal
frequency response of the optical detector. The uniformly sampled
digital signal allows for the application of one or more digital
filters whose cumulative frequency response is the inverse of the
analog electronics' transfer function (see, e.g., U.S. Pat. No.
7,446,878, incorporated herein by reference).
Computing Subsystem 400
[0108] The computing subsystem 400 performs multiple functions such
converting the digitized data obtained from the data acquisition
subsystem 300 to single beam spectra, performing spectral outlier
checks on the single beam spectra, spectral preprocessing in
preparation for prediction of the attribute of interest, prediction
of the attribute of interest, system status checks, all display and
processing requirements associated with the user interface, and
data transfer and storage. FIG. 21 is a schematic representation
that shows the various aspects of a suitable computing subsystem.
In some embodiments, the computing subsystem is contained in a
dedicated personal computer or laptop computer that is connected to
the other subsystems of the invention. In other embodiments, the
computing subsystem is a dedicated, embedded computer.
[0109] After converting the digitized data from the detector to
single beam spectra, the computer system can check the single beam
spectra for outliers or bad scans. An outlier sample or bad scan is
one that violates the hypothesized relationship between the
measured signal and the properties of interest. Examples of outlier
conditions include conditions where the calibrated instrument is
operated outside of the specified operating ranges for ambient
temperature, ambient humidity, vibration tolerance, component
tolerance, power levels, etc. In addition, an outlier can occur if
the composition or concentration of the sample is different than
the composition or concentration range of the samples used to build
the calibration model. The calibration model will be discussed as
part of the calibration subsystem later in this disclosure. Any
outliers or bad scans can be deleted and the remaining good spectra
can be averaged together to produce an average single beam spectrum
for the measurement. The average single beam spectrum can be
converted to absorbance by taking the negative base 10 logarithm
(log 10) of the spectrum. The absorbance spectrum can be scaled by
a single beam spectrum to renormalize the noise.
[0110] The scaled absorbance spectrum can be used to determine the
attribute of interest in conjunction with a calibration model that
is obtained from the calibration subsystem 500. After determination
of the attribute of interest, the computing subsystem 400 can
report the result 830, e.g., to the subject, to an operator or
administrator, to a recording system, or to a remote monitor. The
computing subsystem 400 can also report the level of confidence in
the goodness of the result. If the confidence level is low, the
computing subsystem 400 can withhold the result and ask the subject
to retest. If required, additional information can be conveyed that
directs the user to perform a corrective action. See, e.g., US
Application 20040204868, incorporated herein by reference. The
results can be reported visually on a display, by audio and/or by
printed means. Additionally, the results can be stored to form a
historical record of the attribute. In other embodiments, the
results can be stored and transferred to a remote monitoring or
storage facility via the internet, phone line, or cell phone
service.
[0111] The computing subsystem 400 includes a central processing
unit (CPU), memory, storage, a display and preferably a
communication link. An example of a CPU is the Intel Pentium
microprocessor. The memory can be, e.g., static random access
memory (RAM) and/or dynamic random access memory. The storage can
be accomplished with non-volatile RAM or a disk drive. A liquid
crystal display can be suitable. The communication link can be, as
examples, a high speed serial link, an Ethernet link, or a wireless
communication link. The computer subsystem can, for example,
produce attribute measurements from the received and processed
interferograms, perform calibration maintenance, perform
calibration transfer, run instrument diagnostics, store a history
of measured alcohol concentrations and other pertinent information,
and in some embodiments, communicate with remote hosts to send and
receive data and new software updates.
[0112] The computing system 400 can also contain a communication
link that allows transfer of a subject's alcohol measurement
records and the corresponding spectra to an external database. In
addition, the communication link can be used to download new
software to the computer and update the multivariate calibration
model. The computer system can be viewed as an information
appliance. Examples of information appliances include personal
digital assistants, web-enabled cellular phones and handheld
computers.
Calibration Subsystem 500
[0113] A calibration model is used in connection with the spectral
information in order to obtain alcohol measurements. In some
embodiments, the calibration model is formed by acquiring blood
reference measurements and contemporaneous spectroscopic data on
multiple subjects in a wide variety of environmental conditions. In
these embodiments, spectroscopic data can be acquired from each
subject over a range of blood alcohol concentrations. In other
embodiments, a hybrid calibration model can be to measure the
alcohol concentrations of subject spectra. In this case, the term
hybrid model denotes that a partial least squares (PLS) calibration
model was developed using a combination of in vitro and in vivo
spectral data. The in vitro portion of the data was a 0.1 mm
pathlength transmission spectrum of 500 mg/dL alcohol in water
measured using the non-invasive measurement system configured for
transmission measurements. The transmission spectrum was ratioed to
a 0.1 mm pathlength transmission spectrum of water, converted to
absorbance, and normalized to unit pathlength and
concentration.
[0114] Light propagation through tissue is a complex function of
the diffuse reflectance optical tissue sampler design,
physiological variables, and wavenumber. Consequently, the
pathlength of light through tissue has a wavenumber dependence that
is not encountered in scatter-free transmission measurements. In
order to account for the wavenumber dependence, the interaction of
the optical tissue sampler with the scattering properties of human
tissue was modeled via Monte-Carlo simulation using a commercial
optical ray-tracing software package (TracePro). Using the
resulting model of the photon-tissue interactions, an estimate of
the effective pathlength of light through the dermis and
subcutaneous tissue layers as a function of wavenumber was
generated. The effective pathlength (I.sub.eff) is defined as
l eff ( v ) = i = 1 N l i exp ( - .mu. a ( v ) l i ) i = 1 N l i ,
##EQU00001##
where v is wavenumber, I.sub.l is the pathlength traversed by the
i.sup.th ray in the Monte Carlo simulation [mm], N is the total
number of rays in the simulation, and .sub.a is the
(wavenumber-dependent) absorption coefficient [mm.sup.-1]. Due to
its large absorption in vivo, water is the only analyte that has a
significant effect on the effective pathlength. Therefore, for the
purposes of the effective pathlength calculation, the absorption
coefficients used were those of water at physiological
concentrations. The alcohol absorbance spectrum (as measured in
transmission) was then scaled by the computed path function to form
a corrected alcohol spectrum representative of the wavenumber
dependent pathlength measured by the diffuse reflectance optical
sampler. FIG. 22 shows the alcohol absorbance spectrum before and
after correction by the path function. The solid line is before
correction; the dotted line is after correction. This corrected
spectrum formed the base spectrum for the mathematical addition of
alcohol to the calibration spectra.
[0115] The in vivo data comprised noninvasive tissue spectra
collected from persons who had not consumed alcohol. A hybrid model
was formed by adding the alcohol pure component spectrum, weighted
by various alcohol "concentrations" (ranging from 0 to 160 mg/dL),
to the noninvasive tissue spectral data. The PLS calibration model
was built by regressing the synthetic alcohol concentrations on the
hybrid spectral data. FIG. 23 is a schematic representation of a
hybrid calibration formation process. The hybrid calibration in
this work used approximately 1500 non-invasive tissue spectra that
were collected from 133 subjects over three months.
[0116] The use of hybrid calibration models, rather than
calibration models built from spectra acquired from subjects who
have consumed alcohol, can provide significant advantages. The
hybrid modeling process makes it possible to generate calibration
spectra that contain higher concentrations (up to 160 mg/dL in this
work) of alcohol than would be considered safe for consumption in a
human subject study (120 mg/dL is considered a safe upper limit).
This can result in a stronger calibration with a wider range of
analyte concentrations that is able to predict higher alcohol
concentrations more accurately. This can be important because
alcohol concentrations observed in the field can be more than
double the maximum safe dosage in a clinical research setting. The
hybrid calibration process also allows the prevention of
correlations between alcohol and the spectral interferents in
tissue. For example, the random addition of alcohol signal to the
calibration spectra prevents alcohol concentration from being
correlated with water concentration. Thus, the hybrid approach
prevents the possibility that the measurement could spuriously
track changes in tissue water content instead of alcohol
concentration.
[0117] Once formed, it is desirable that a calibration remain
stable and produce accurate attribute predictions over an extended
period of time. This process is referred to as calibration
maintenance and can be comprised of multiple methods that can be
used individually or in conjunction. The first method is to create
the calibration in a manner that inherently makes it robust.
Several different types of instrumental and environmental variation
can affect the prediction capability of a calibration model. It is
possible and desirable to reduce the magnitude of the effect of
instrumental and environmental variation by incorporating this
variation into the calibration model.
[0118] It is difficult, however, to span the entire possible range
of instrument states during the calibration period. System
perturbations can result in the instrument being operated outside
the space of the calibration model. Measurements made while the
instrument is in an inadequately modeled state can exhibit
prediction errors. In the case of in vivo optical measurements of
medically significant attributes, these types of errors can result
in erroneous measurements that degrade the utility of the system.
Therefore it is often advantageous to use additional calibration
maintenance techniques during the life of the instrument in order
to continually verify and correct for the instrument's status.
[0119] Examples of problematic instrument and environmental
variation include, but are not limited to: changes in the levels of
environmental interferents such as water vapor or CO.sub.2 gas,
changes in the alignment of the instrument's optical components,
fluctuations in the output power of the instrument's illumination
system, and changes in the spatial and angular distribution of the
light output by the instrument's illumination system.
[0120] Calibration maintenance techniques are discussed in U.S.
Pat. No. 6,983,176, "Optically Similar Reference Samples and
Related Methods for Multivariate Calibration Models Used in Optical
Spectroscopy"; U.S. Pat. No. 7,092,832, "Adaptive Compensation for
Measurement Distortions in Spectroscopy"; U.S. Pat. No. 7,098,037,
"Accommodating Subject and Instrument Variations in Spectroscopic
Determinations", and U.S. Pat. No. 7,202,091, "Optically Similar
Reference Samples", each of which is incorporated herein by
reference. In some of the disclosed methods, an environmentally
inert non-tissue sample, such as an integrating sphere, that may or
may not contain the attribute of interest is used in order to
monitor the instrument over time. The sample can be incorporated
into the optical path of the instrument or interface with the
sampling subsystem in a manner similar to that of tissue
measurements. The sample can be used in transmission or in
reflectance and can contain stable spectral features or contribute
no spectral features of its own. The material can be a solid,
liquid, or gel material as long as its spectrum is stable or
predicable over time. Any unexplained change in the spectra
acquired from the sample over time indicate that the instrument has
undergone a perturbation or drift due to environmental effects. The
spectral change can then be used to correct subsequent tissue
measurements in humans in order to ensure and accurate attribute
measurement.
[0121] Another means for achieving successful calibration
maintenance is to update the calibration using measurements
acquired on the instrument over time. Usually, knowledge of the
reference value of the analyte property of interest is required in
order to perform such an update. However, in some applications, it
is known that the reference value is usually, but not always, a
specific value. In this case, this knowledge can be used to update
the calibration even though the specific value of the analyte
property is not known for each measurement. For example, in alcohol
screening in residential treatment centers, the vast majority of
measurements are performed on individuals that have complied with
their alcohol consumption restrictions and therefore have an
alcohol concentration of zero. In this case, the alcohol
concentration measurement or the associated spectrum obtained from
the device of the present invention can be used in conjunction with
a presumed zero as a reference value. Thus, the calibration can be
updated to include new information as it is acquired in the field.
This approach can also be used to perform calibration transfer as
measurements with presumed zeros can be used at the time of system
manufacture or installation in order to remove any system-specific
bias in the analyte property measurements of interest. The
calibration maintenance update or calibration transfer
implementation can be accomplished by a variety of means such as,
but not limited to, orthogonal signal correction (OSV), orthogonal
modeling techniques, neural networks, inverse regression methods
(PLS, PCR, MLR), direct regression methods (CLS), classification
schemes, simple median or moving windows, principal components
analysis, or combinations thereof.
[0122] Once a calibration is formed, it is often desirable to
transfer the calibration to all existing and future units. This
process is commonly referred to as calibration transfer. While not
required, calibration transfer prevents the need for a calibration
to be determined on each system that is manufactured. This
represents a significant time and cost savings that can affect the
difference between success or failure of a commercial product.
Calibration transfer arises from the fact that optical and
electronic components vary from unit to unit which, in aggregate,
can result in a significant difference in spectra obtained from
multiple instruments. For example, two light sources can have
different color temperatures thereby resulting in a different light
distribution for the two sources. The responsivity of two detectors
can also differ significantly, which can result in additional
spectral differences.
[0123] Similar to calibration maintenance, multiple methods can be
used in order to effectively achieve calibration transfer. The
first method is to build the calibration with multiple instruments.
The presence of multiple instruments allows the spectral variation
associated with instrument differences to be determined and made
orthogonal to the attribute signal during the calibration formation
process. While this does approach reduces the net attribute signal,
it can be an effective means of calibration transfer.
[0124] Additional calibration transfer methods involve explicitly
determining the difference in the spectral signature of a system
relative to those used to build the calibration. In this case, the
spectral difference can then be used to correct a spectral
measurement prior to attribute prediction on a system or it can be
used to correct the predicted attribute value directly. The
spectral signature specific to an instrument can be determined from
the relative difference in spectra of a stable sample acquired from
the system of interest and those used to build the calibration. The
samples described in the calibration maintenance section are also
applicable to calibration transfer. See, e.g. U.S. Pat. No.
6,441,388, "Method and Apparatus for Spectroscopic Calibration
Transfer", incorporated herein by reference.
ADDITIONAL ASPECTS OF THE PRESENT INVENTION
Alcohol Measurement Modalities
[0125] Depending on the application of interest, the measurement of
an analyte property can be considered in terms of two modalities.
The first modality is "walk up" or "universal" and represents an
analyte property determination wherein prior measurements of the
sample (e.g. subject) are not used in determining the analyte
property from the current measurement of interest. In the case of
measuring in vivo alcohol, driving under the influence enforcement
would fall into this modality as in most cases the person being
tested will not have been previously measured on the alcohol
measurement device. Thus, no prior knowledge of that person is
available for use in the current determination of the analyte
property.
[0126] The second modality is termed "enrolled" or "tailored" and
represents situations where prior measurements from the sample or
subject are available for use in determining the analyte property
of the current measurement. An example of an environment where this
modality can be applied is vehicle interlocks where a limited
number of people are permitted to drive or operate a vehicle or
machine. Additional information regarding embodiments of enrolled
and tailored applications can be found in U.S. Pat. Nos. 6,157,041
and 6,528,809, titled "Method and Apparatus for Tailoring
Spectroscopic Calibration Models", each of which is incorporated
herein by reference. In enrolled applications, the combination of
the analyte property measurement with a biometric measurement can
be particularly advantageous as the same spectroscopic measurement
can assess if a prospective operator is authorized to use the
equipment or vehicle via the biometric while the analyte property
can access their fitness level (e.g. sobriety).
Methods for Determining Biometric Verification or Identification
from Spectroscopic Signals
[0127] Biometric identification describes the process of using one
or more physical or behavioral features to identify a person or
other biological entity. There are two common biometric modes:
identification and verification. Biometric identification attempts
to answer the question of, "do I know you?" The biometric
measurement device collects a set of biometric data from a target
individual. From this information alone it assesses whether the
person was previously enrolled in the biometric system. Systems
that perform the biometric identification task, such as the FBI's
Automatic Fingerprint Identification System (AFIS), are generally
very expensive (several million dollars or more) and require many
minutes to detect a match between an unknown sample and a large
database containing hundreds of thousands or millions of entries.
In biometric verification the relevant question is, "are you who
you say you are?" This mode is used in cases where an individual
makes a claim of identity using a code, magnetic card, or other
means, and the device uses the biometric data to confirm the
identity of the person by comparing the target biometric data with
the enrolled data that corresponds with the purported identity. The
present apparatus and methods for monitoring the presence or
concentration of alcohol or substances of abuse in controlled
environments can use either biometric mode.
[0128] There also exists at least one variant between these two
modes that is also suitable for use in the present invention. This
variant occurs in the case where a small number of individuals are
contained in the enrolled database and the biometric application
requires the determination of only whether a target individual is
among the enrolled set. In this case, the exact identity of the
individual is not required and thus the task is somewhat different
(and often easier) than the identification task described above.
This variant might be useful in applications where the biometric
system is used in methods where the tested individual must be both
part of the authorized group and sober but their specific identity
is not required. The term "identity characteristic" includes all of
the above modes, variants, and combinations or variations
thereof.
[0129] There are three major data elements associated with a
biometric measurement: calibration, enrollment, and target spectral
data. The calibration data are used to establish spectral features
that are important for biometric determinations. This set of data
consists of series of spectroscopic tissue measurements that are
collected from an individual or individuals of known identity.
Preferably, these data are collected over a period of time and a
set of conditions such that multiple spectra are collected on each
individual while they span nearly the full range of physiological
states that a person is expected to go through. In addition, the
instrument or instruments used for spectral collection generally
should also span the full range of instrumental and environmental
effects that it or sister instruments are likely to see in actual
use. These calibration data are then analyzed in such a way as to
establish spectral wavelengths or "factors" (i.e. linear
combinations of wavelengths or spectral shapes) that are sensitive
to between-person spectral differences while minimizing sensitivity
to within-person, instrumental (both within- and
between-instruments), and environmental effects. These wavelengths
or factors are then used subsequently to perform the biometric
determination tasks.
[0130] The second major set of spectral data used for biometric
determinations is the enrollment spectral data. The purpose of the
enrollment spectra for a given subject or individual is to generate
a "representation" of that subject's unique spectroscopic
characteristics. Enrollment spectra are collected from individuals
who are authorized or otherwise required to be recognized by the
biometric system. Each enrollment spectrum can be collected over a
period of seconds or minutes. Two or more enrollment measurements
can be collected from the individual to ensure similarity between
the measurements and rule out one or more measurements if artifacts
are detected. If one or more measurements are discarded, additional
enrollment spectra can be collected. The enrollment measurements
for a given subject can be averaged together, otherwise combined,
or stored separately. In any case, the data are stored in an
enrollment database. In some cases, each set of enrollment data are
linked with an identifier (e.g. a password or key code) for the
persons on whom the spectra were measured. In the case of an
identification task, the identifier can be used for record keeping
purposes of who accessed the biometric system at which times. For a
verification task, the identifier is used to extract the proper set
of enrollment data against which verification is performed.
[0131] The third and final major set of data used for the biometric
system is the spectral data collected when a person attempts to use
the biometric system for identification or verification. These data
are referred to as target spectra. They are compared to the
measurements stored in the enrollment database (or subset of the
database in the case of identity verification) using the
classification wavelengths or factors obtained from the calibration
set. In the case of biometric identification, the system compares
the target spectrum to all of the enrollment spectra and reports a
match if one or more of the enrolled individual's data is
sufficiently similar to the target spectrum. If more than one
enrolled individual matches the target, then either all of the
matching individuals can be reported, or the best match can be
reported as the identified person. In the case of biometric
verification, the target spectrum is accompanied by an asserted
identity that is collected using a magnetic card, a typed user name
or identifier, a transponder, a signal from another biometric
system, or other means. The asserted identity is then used to
retrieve the corresponding set of spectral data from the enrollment
database, against which the biometric similarity determination is
made and the identity verified or denied. If the similarity is
inadequate, then the biometric determination is cancelled and a new
target measurement may be attempted.
[0132] In one method of verification, principle component analysis
is applied to the calibration data to generate spectral factors.
These factors are then applied to the spectral difference taken
between a target spectrum and an enrollment spectrum to generate
Mahalanobis distance and spectral residual magnitude values as
similarity metrics. Identify is verified only if the aforementioned
distance and magnitude are less than a predetermined threshold set
for each. Similarly, in an example method for biometric
identification, the Mahalanobis distance and spectral residual
magnitude are calculated for the target spectrum relative each of
the database spectra. The identity of the person providing the test
spectrum is established as the person or persons associated with
the database measurement that gave the smallest Mahalanobis
distance and spectral residual magnitude that is less than a
predetermined threshold set for each.
[0133] In an example method, the identification or verification
task is implemented when a person seeks to perform an operation for
which there are a limited number of people authorized (e.g.,
perform a spectroscopic measurement, enter a controlled facility,
pass through an immigration checkpoint, etc.). The person's
spectral data is used for identification or verification of the
person's identity. In this example method, the person initially
enrolls in the system by collecting one or more representative
tissue spectra. If two or more spectra are collected during the
enrollment, then these spectra can be checked for consistency and
recorded only if they are sufficiently similar, limiting the
possibility of a sample artifact corrupting the enrollment data.
For a verification implementation, an identifier such as a PIN
code, magnetic card number, username, badge, voice pattern, other
biometric, or some other identifier can also be collected and
associated with the confirmed enrollment spectrum or spectra.
[0134] In subsequent use, biometric identification can take place
by collecting a spectrum from a person attempting to gain
authorization. This spectrum can then be compared to the spectra in
the enrolled authorization database and an identification made if
the match to an authorized database entry was better than a
predetermined threshold. The verification task is similar, but can
require that the person present the identifier in addition to a
collected spectrum. The identifier can then be used to select a
particular enrollment database spectrum and authorization can be
granted if the current spectrum is sufficiently similar to the
selected enrollment spectrum. If the biometric task is associated
with an operation for which only a single person is authorized,
then the verification task and identification task are the same and
both simplify to an assurance that the sole authorized individual
is attempting the operation without the need for a separate
identifier.
[0135] The biometric measurement, regardless of mode, can be
performed in a variety of ways including linear discriminant
analysis, quadratic discriminant analysis, K-nearest neighbors,
neural networks, and other multivariate analysis techniques or
classification techniques. Some of these methods rely upon
establishing the underlying spectral shapes (factors, loading
vectors, eigenvectors, latent variables, etc.) in the intra-person
calibration database, and then using standard outlier methodologies
(spectral F ratios, Mahalanobis distances, Euclidean distances,
etc.) to determine the consistency of an incoming measurement with
the enrollment database. The underlying spectral shapes can be
generated by multiple means as disclosed herein.
[0136] First, the underlying spectral shapes can be generated based
upon simple spectral decompositions (eigen analysis, Fourier
analysis, etc.) of the calibration data. The second method of
generating underlying spectral shapes relates to the development of
a generic model as described in U.S. Pat. No. 6,157,041, entitled
"Methods and Apparatus for Tailoring Spectroscopic Calibration
Models," which is incorporated by reference. In this application,
the underlying spectral shapes are generated through a calibration
procedure performed on intra-person spectral features. The
underlying spectral shapes can be generated by the development of a
calibration based upon simulated constituent variation. The
simulated constituent variation can model the variation introduced
by real physiological or environmental or instrumental variation or
can be simply be an artificial spectroscopic variation. It is
recognized that other means of determining underlying shapes would
be applicable to the identification and verification methods of the
present invention. These methods can be used either in conjunction
with, or in lieu of the aforementioned techniques.
Calibration Check Samples
[0137] In addition to disposables to ensure subject safety,
disposable calibration check samples can be used to verify that the
instrument is in proper working condition. In many commercial
applications of alcohol measurements, the status of the instrument
must be verified to ensure that subsequent measurements will
provide accurate alcohol concentrations or attribute estimates. The
instrument status is often checked immediately prior to a subject
measurement. In some embodiments, the calibration check sample can
include alcohol. In other embodiments, the check sample can be an
environmentally stable and spectrally inert sample, such as an
integrating sphere. The check sample can be a gas or liquid that is
injected or flowed through a spectroscopic sampling chamber. The
check sample can also be a solid, such as a gel, that may contain
alcohol. The check sample can be constructed to interface with the
sampling subsystem or it can be incorporated into another area of
the optical path of the system. These examples are meant to be
illustrative and are not limiting to the various possible
calibration check samples.
Direction of Change (DOC) and Rate of Change (ROC)
[0138] The present invention also comprises methods for measurement
of the direction and magnitude of concentration changes of tissue
constituents, such as alcohol, using spectroscopy. The non-invasive
measurement obtained from the current invention is inherently
semi-time resolved. This allows attributes, such as alcohol
concentration, to be determined as a function of time. The time
resolved alcohol concentrations can then be used to determine the
rate and direction of change of the alcohol concentration. In
addition, the direction of change information can be used to
partially compensate for any difference in blood and non-invasive
alcohol concentration that is caused by physiological kinetics. See
U.S. Pat. No. 7,016,713, "Determination of Direction and Rate of
Change of an Analyte", and US Application 20060167349, "Apparatus
for Noninvasive Determination of Rate of Change of an Analyte",
each of which is incorporated herein by reference. A variety of
techniques for enhancing the rate and direction signal have been
uncovered. Some of these techniques include heating elements,
rubrifractants, and index-matching media. They should not be
interpreted as limiting the present invention to these particular
forms of enhancement or equilibration. These enhancements are not
required to practice the present invention, but are included for
illustrative purposes only.
Subject Safety
[0139] Another aspect of non-invasive alcohol measurements is the
safety of the subjects during the measurements. In order to prevent
measurement contamination or transfer of pathogens between subjects
it can be desirable, but it is not necessary, to use disposable
cleaning agents and/or protective surfaces in order to protect each
subject and prevent fluid or pathogen transfer between subjects.
For example, in some embodiments an isopropyl wipe can be used to
clean each subject's sampling site and/or the sampling subsystem
surface prior to measurement. In other embodiments, a disposable
thin film of material such as ACLAR can be placed between the
sampling subsystem and the subject prior to each measurement in
order to prevent physical contact between the subject and the
instrument. In other embodiments, both cleaning and a film can be
used simultaneously. As mentioned in the sampling subsystem portion
of this disclosure, the film can also be attached to a positioning
device and then applied to the subject's sampling site. In this
embodiment, the positioning device can interface with the sampling
subsystem and prevent the subject from moving during the
measurement while the film serves its protective role.
Topical Interferents
[0140] In subject measurements the presence of topical interferents
on the sampling site is a significant concern. Many topical
interferents have spectral signatures in the near infrared region
and can therefore contribute significant measurement error when
present. The present invention deals with the potential for topical
interferents in three ways that can be used individually or in
conjunction. FIG. 24 shows a flow diagram that describes a method
for combining the three topical interferent mitigation approaches
into one combined process. First, a disposable cleaning agent
similar to that described in the subject safety section can be
used. The use of the cleaning agent can either be at the discretion
of the system operator or a mandatory step in the measurement
process. Multiple cleaning agents can also be used that
individually target different types of topical interferents. For
example, one cleaning agent can be used to remove grease and oils,
while another could be used to remove consumer goods such as
cologne or perfume. The cleaning agents can remove topical
interferents prior to the attribute measurement in order to prevent
them from influencing the accuracy of the system.
[0141] A second method for mitigating the presence of topical
interferents is to determine if one or more interferents is present
on the sampling site. The multivariate calibration models used in
the calibration subsystem offer inherent outlier metrics that yield
important information regarding the presence of un-modeled
interferents (topical or otherwise). As a result, they provide
insight into the trustworthiness of the attribute measurement. FIG.
25 shows example outlier metric values from noninvasive
measurements using the present invention acquired during the
clinical studies. All of the large metric values (clearly separated
from the majority of the points) correspond to measurements where
grease had been intentionally applied to the subject's sampling
site. These metrics do not specifically identify the cause of the
outlier, but they do indicate that the associated attribute
measurement is suspect. An inflated outlier metric value (a value
beyond a fixed threshold, for example) can be used to trigger a
fixed response such as a repeat of the measurement, application of
an alternative calibration model, or a sampling site cleaning
procedure. This is represented in FIG. 24 as the "Spectral Check
OK" decision point.
[0142] The final topical interferent mitigation method involves
adapting the calibration model to include the spectral signature of
the topical interferent. The adapted calibration model can either
be created on demand or selected from an existing library of
calibration models. Each calibration in the library can be targeted
at mitigating a different interferent or class of interferents such
as oils. In some embodiments, the appropriate calibration model can
be chosen based on the portion of an acquired spectrum that is
unexplained by the original calibration model. This portion of the
spectrum is referred to as the calibration model residual. Because
each topical interferent or class of interferents has a unique near
infrared spectrum, the calibration model residual can be used to
identify the topical interferent.
[0143] The model residual or the pure spectrum (obtained from a
stored library) of the interferents can then be incorporated into
the spectra used to form the calibration. The multivariate
calibration is then reformed with the new spectra such that the
portion of the attribute signal that is orthogonal to the
interferent can be determined. The new calibration model is then
used to measure the attribute of interest and thereby reduce the
effects of the topical interferent on attribute measurement
accuracy. The resulting model will reduce the effect of the
interferent on the alcohol measurement at the expense of
measurement precision when no interferents are present. This
process is referred to as calibration immunization. The
immunization process is similar to the hybrid calibration formation
process shown in FIG. 24, but includes the additional step of the
mathematical addition of the interferent's spectral variation. It
should be noted that, due to the impact of the immunization process
on measurement precision, it can be desirable to identify possible
interferents for each measurement and immunize specifically against
them rather than attempt to develop a calibration that is immunized
against all possible interferents. Additional details can be found
in US 20070142720, "Apparatus and methods for mitigating the
effects of foreign interferents on analyte measurements in
spectroscopy", incorporated herein by reference.
Novel Blackbody Light Sources
[0144] It is important to note that the present invention also
envisions several embodiments of alcohol measurement systems
incorporating broadband light sources rather than narrowband solid
state light sources. An example light source is a ceramic element
such as those commonly used as igniters for furnaces and stoves.
These light sources have a lower color temperature than standard
filament lamps and are therefore more efficient in the
near-infrared spectral region. These sources also have
comparatively large emissive surfaces that are less sensitive to
spatial effects that are encountered throughout the lifetime of the
light source. An additional advantage of igniter-based light
sources is a substantially longer lifetime when compared to
filament lamps. In these embodiments, the broad blackbody source
can be converted to multiple, narrow light sources using optical
filters such as, but not limited to, linearly variable filters
(LVF's), dielectric stacks, distributed Bragg gratings, photonic
crystal lattice filters, polymer films, absorption filters,
reflection filters, etalons, dispersive elements such as prisms and
gratings, and quantum dot filters. The resulting multiple bands of
wavelengths can be modulated by a Fourier scheme or Hadamard
mask.
[0145] Some embodiments of the present invention eliminate the
drawbacks of filament-based light sources by replacing them with
alternative sources of IR and NIR light. Ceramic-based blackbody
light sources and semiconductor-based light sources offer several
advantages including elimination of the glass envelope, higher
efficiency (less light in unwanted spectral regions), and more
stable spatial emission. Consequently, the ceramic and
semiconductor light sources offer an improved foundation for
subsequent spatial and angular homogenization. Furthermore, due to
the improved optical efficiency, these light sources do not require
undesired wavelengths to be optically filtered prior to sample
illumination. The reduction of the illumination source as an
instrument variance or interferent has been found to improve the
ability to build an optical system and model which can accurately
predict analyte concentrations in turbid media such as tissue. Some
embodiments of the present invention provide this illumination
stability by collecting and modifying the output emitted by a light
source prior to illuminating the sample under investigation.
[0146] Some embodiments of the present invention relate to methods
for minimizing spectroscopic variances due to radiation emitters of
angular and/or spatial homogenization. Angular homogenization is
any process that takes an arbitrary angular distribution, or
intensity (W/sr), of emitted radiation, and creates a more uniform
angular distribution. Spatial homogenization is the process of
creating a more uniform distribution of irradiance (W/m.sup.2)
across an output or exit face.
[0147] All practical light sources produce a non-uniform irradiance
distribution due to their physical structure. Thus, radiation
emitter differences (e.g., a different source) will result in
different non-uniform irradiance distributions. These differences
in irradiance distribution can translate into spectroscopic
differences between light sources. Thus, it can be useful to take
different irradiance distributions due to emitter differences and
create similar or ideally the same irradiance distribution. An
example method of creating similar irradiance distributions is to
create a uniform irradiance distribution.
[0148] Differences in the radiation emitter can also result in
differences in angular distribution. As above, it can be useful to
create an illumination system where radiation emitter differences
do not affect the angular distribution observed by the sample or at
the input to the spectrometer. One mechanism is to create a uniform
angular distribution. An ideal angular homogenizer would uniformly
distribute the light over a sphere (4 pi sr) regardless of the
angular distribution from the emitter. An ideal reflective angular
homogenizer would uniformly distribute light over a hemisphere (2
pi sr). Due to the fact that other optical components in the system
must collect light within a defined numerical aperture, ideal
homogenizers are typically very inefficient. Thus, the instrument
designer must weigh the benefits of angular homogenization with
loss in optical efficiency. Regardless of the specific embodiment,
angular homogenization can be a critical component in the
realization of an illumination system that has reduced sensitivity
to emitter differences.
[0149] The present invention provides a system for producing
spatially and angularly homogenized light from an irregular emitter
and using the homogenized light for spectral analysis. The
resulting homogenized radiation illuminates the sample or sampler
in a consistent and reproducible form, thus allowing for accurate
and dependable spectroscopic measurements.
[0150] An additional benefit of the current invention is spatial
homogenization. The color temperature of filament and ceramic light
sources is not spatially uniform across the entire emissive area of
the source. Thus, color temperature variations across the filament
will result in spectral differences across the filament length.
These spectral differences due to color temperature variations or
other filament differences can be different between emitters and
can change over time. Thus, it can also be important to take the
different spectral distribution due to spatial heterogeneity of the
emitter and create a preferably uniform spectral distribution at
all spatial locations at the output of the illumination system.
[0151] Advantages of the present invention can be illustrated by
the familiar occurrence of routine maintenance to a spectrometer.
It is common for radiant light sources to burn out. Although
application dependent, the replacement of the light source can
result in analyte measurement errors and can necessitate
recalibration of the spectrometer following the light source
replacement. In systems intended for commercial use by unskilled
operators, recalibration is not desired. With the present
invention, however, differences in the light source are irrelevant
and proper performance of the optical measurement system is
maintained. Regardless of the spatial and angular characteristics
of the radiation emitted by the light source, the use of the
illumination systems of the present invention will result in
radiation incident on the sample which remains substantially
spatially and angularly homogenized. Thus, a light source change
will not detract from the accuracy and dependability of molecular
absorbance measurements using the present invention.
[0152] The present invention further specifies a system for
providing illumination to biological tissue samples. More
specifically, the system is particularly suited for spectroscopic
illumination of biological tissues for determining and quantifying
the concentration of specific analytes within or other
characteristics of the tissue. The present invention enables a
practitioner to construct and operate an illumination device that
permits measurements with a high signal-to-noise ratio (SNR) while
minimizing thermal damage to biological tissue. With a high SNR,
chemometric models can be developed for differentiating between a
particular analyte and interferents similar to that analyte.
[0153] The present invention allows for spectroscopic analysis of
turbid media by satisfying the following conditions:
(1) The radiation emitted by the present invention contains
wavelengths useful for measuring the analyte of interest. The
radiation can be continuous versus wavelength, in locally
continuous bands, or selected to particular wavelengths. The result
is radiation that encompasses the wavelength regions that contain
the NIR or IR spectral "fingerprint" for the analyte of interest.
For the noninvasive measurement of ethanol using NIR spectroscopy,
this wavelength region spans approximately from 1.0 to 2.5 .mu.m.
(2) The radiation emitted by the present invention is of
sufficiently high spectral radiance to provide a high
signal-to-noise ratio in the spectral region of interest. In the
measurement of ethanol using NIR spectroscopy, for example, the
radiation from a ceramic light source or one or more semiconductor
light sources concentrated with one or more optical elements, such
as lenses and or mirrors, will provide a spectral radiance that
satisfies this condition. (3) The spectral radiance is generally
invariant when subjected to changes in the spectral excitance of
the emitter. Reasonably expected changes in the spectral excitance
are those due to rotation and/or small translation of the emitter,
or replacement of the emitter with another emitter of the same
general construction.
[0154] By satisfying the above conditions, the ceramic-based light
sources of the present invention eliminate the need for
recalibration due to illumination variability (light source
changes, source aging, source rotation or movement) or, in some
embodiments, development of a chemometric model that compensates
for such changes. Simple maintenance such as replacing the light
source do not necessitate recalibration or the development of
chemometric models sensitive to light source changes. Furthermore,
rotations and translations of the light source caused by jolts,
bumps, and other similar vibrations can have minimal effects on the
accuracy of a test.
Advantages of Semiconductor Light Source Alternatives
[0155] Most light sources used in spectroscopy are blackbody
radiators. The light emitted by a blackbody radiator is governed by
Plank's law which indicates that the intensity of the light emitted
is a function of wavelength and the temperature of the
blackbody.
[0156] FIG. 26 shows normalized NIR spectra of 1300 and 3000 K
blackbody radiators over the 100-33000 cm.sup.-1 (100-0.3 microm)
range with the 4000-8000 cm.sup.-1 (2.5-1.25 microm) range used by
the TruTouch device shaded. 1300 K is a reasonable temperature for
the ceramic-based blackbody light source the TruTouch technology
currently employs and 3000 K is a reasonable temperature for Quartz
Tungsten Halogen (QTH) lamps which are often employed in
spectroscopic applications. FIG. 26 indicates that the optical
efficiency of both blackbody light sources is not ideal in that a
significant amount of light is emitted at wavelengths outside the
TruTouch region of interest with the optical efficiency of the
ceramic light source being 58% and the QTH only 18%.
[0157] In addition to optical efficiency, blackbody light sources
can have poor electrical efficiency. Practical blackbody light
sources require a significant amount of electrical power, not all
of which is converted to emitted light. Electrical and optical
power measurements on hundreds of ceramic blackbody light sources
that show an average of 1.1 W of optical power at an average of 24
W of electrical power (4.4% electrical efficiency). When combined
with the optical efficiency of 58%, the overall efficiency of the
ceramic blackbody is approximately 2.5%. In other words, at 24 W of
electrical power, approximately 0.6 W of optical power is emitted
in the 4000 to 8000 cm.sup.-1 region of interest. Further losses
are incurred as not all light emitted by the source is collected by
the remainder of the optical system.
[0158] As indicated by the low electrical efficiency, most of the
applied electrical power is converted to heat which has a
detrimental beyond the higher than desired power requirement. The
heat generated by the blackbody light source can have an impact on
the thermal state and stability of the spectroscopic measurement
device. Consequently, in some situations the device must be powered
on and allowed to reach thermal equilibrium prior to performing
measurements. The equilibration time associated with the blackbody
light source can range from minutes to hours which can be
disadvantageous in some situations.
[0159] Blackbody light sources exhibit an aging effect as the
material resistance changes. From an optical perspective, there are
to significant implications associated with the light source aging.
First, as the resistance increases the amount of optical power
emitted decreases. FIG. 27 shows the measured intensity over time
observed for a demonstrative ceramic blackbody light source that
exhibits a 50% reduction in power over 3500 hours. The intensity
degradation over time tends to be exponential in nature and can
necessitate replacement of the light source at regular intervals
which can be disadvantageous in some deployment environments.
Second, the temperature of the light source changes which alters
the distribution of the light as a function of wavelength.
Depending on the severity of the color temperature change, the
stability of the spectroscopic device over time can be
impacted.
[0160] LEDs and other solid state light sources, in contrast, are
narrower in their emission profiles, which allow the ability to
concentrate the emitted light in the 4000 to 8000 cm.sup.-1 region
of interest.
[0161] FIG. 28 shows the spectral emission profiles of several
commercially available NIR LEDs that were obtained from their
respective product data sheets. The range of available LEDs allows
the investigation of their combination to form a light source
system that spans the 4000-8000 cm.sup.-1 region of interest while
minimizing light output at lower and higher wavenumber that are not
employed by the desired measurement. Thus, the resulting system
will exhibit an improved optical efficiency. It is important to
note, that in contrast to other embodiments involving modulation
schemes previously discussed, the objective of these embodiments of
solid state light sources is to use multiple solid state light
sources to collectively mimic the optical properties of a blackbody
light source in a more efficient package.
[0162] FIG. 28 demonstrates that no single currently available LED
can viably replace a blackbody light source as the spectral
emission profiles do not span the entire 4000 to 8000 cm.sup.-1
region of interest. Consequently, multiple LEDs can be optically
combined in order to generate a suitable light source subsystem.
The number of LED's that can be incorporated into the light source
subsystem is ultimately determined by the area and angular
acceptance of the optical system and the size and angular
divergence of the individual LEDs. While the determination of the
optimal combination of LEDs is an extensive effort involving
optical and mechanical design and spectroscopic analysis a
simplified approach is shown in FIG. 35 that does not invoke any
optical design or photon collection efficiencies (which are
different for blackbody and LED light sources), nor the design
required to optically combine the outputs of multiple LEDs. The
blackbody line in FIG. 35 corresponds to a 1300.degree. K blackbody
light source, and is the desired target for the LED combination in
this example. The dotted lines are the individual profiles of each
type of LED and the sum line is the sum of the dotted lines which
assumes no losses are encountered in the optical combination. It is
further assumed in this example that the magnitude of each dotted
line can be practically influenced by either changing the input
power to the respective LED or by adding more LEDs of that type.
Furthermore, within a given spectral region of interest, some
wavelengths can be more important than others to a given
application such as alcohol measurements in tissue. The narrow
profiles exhibited by the LEDs can allow better fine tuning of the
relative intensities of the wavelengths as compared to blackbody
light sources.
[0163] LEDs do not critically fail in any manner similar to
filament lamps. Instead they exhibit an intensity degradation over
time. As a result, the lifetimes of LEDs are measured in terms of
the time in hours required for the average LED of a given type to
reach 50% of its original intensity (T50). The lifetimes of LEDs,
for example, range from 50,000 to 100,000 hours. As a result, LEDs
offer the potential for a 10.times. improvement in light source
life and a corresponding reduction in the need for routine
maintenance relative to blackbody light sources.
[0164] LEDs and semiconductor lasers such as VCSELs can have small
emissive areas when compared to their blackbody counterparts that
is driven by the size of the semiconductor die itself. The photon
emission cannot occur outside of the area of the die as it is
generated within the semiconductor structure. The small size (a
common emissive area is a 0.3 mm.times.0.3 mm square or 0.09
mm.sup.2) can be advantageous in that any heterogeneity within that
area will be insignificant relative to size of the output of the
illumination system (which can be several mm.sup.2 or larger
depending on the application). Thus, as long as the die (or dies if
multiple semiconductors are employed) do not physically move, the
spatial output will be very stable. Subsequent spatial homogenizers
can then uniformly distribute the light emitted by the die across
the entire area of the illumination system output.
[0165] Another advantage of semiconductor light sources such as
LEDs is the ability to incorporate more than one dye into the same
physical package. As the output of an LED is typically spectrally
narrower than a blackbody light source, multiple LEDs of different
types (e.g. peak wavelength of emission) can be combined to
increase the spectral range of the illumination system.
Furthermore, additional LEDs of the same type can be included in
order to increase the optical power at the corresponding
wavelengths. Such approaches allow a high level of control over
both the specific wavelengths and relative intensities emitted by
an illumination system. This can be used to accentuate wavelengths
important to a given analyte of interest such as alcohol, while
reducing the output at less-important wavelengths. Whether the set
of LEDs is all of the same type or a mixture, up to several hundred
LEDs can be incorporated into the same package while retaining an
integrated optical area consistent with use in noninvasive analyte
measurements such as alcohol.
[0166] Another advantage of semiconductor light sources is the
ability to select which light sources are on at a given time as
well as tune their output via voltage or current and temperature.
Consequently, a single illumination system can be optimized for
measurements of multiple analytes. For example, when measuring
alcohol in tissue a given set of LEDs can be activated. Likewise, a
different set can be activated when measuring a different analyte
such as cholesterol or glucose.
Methods for Spatial and Angular Homogenization
[0167] Light homogenizers such as optical diffusers, light pipes,
and other scramblers can be incorporated into some embodiments of
the illumination/modulation subsystem 100 in order to provide
reproducible and, preferably, uniform radiance at the input of the
tissue sampling subsystem 200. Uniform radiance can ensure good
photometric accuracy and even illumination of the tissue. Uniform
radiance can also reduce errors associated with manufacturing
differences between light sources. Uniform radiance can be utilized
in the present invention for achieving accurate and precise
measurements. See, e.g., U.S. Pat. No. 6,684,099, which is
incorporated herein by reference.
[0168] A ground glass plate is an example of an optical diffuser.
The ground surface of the plate effectively scrambles the angle of
the radiation emanating from the light source and its transfer
optics. A light pipe can be used to homogenize the intensity of the
radiation such that it is spatially uniform at the output of the
light pipe. In addition, light pipes with a double bend will
scramble the angles of the radiation. For creation of uniform
spatial intensity and angular distribution, the cross section of
the light pipe should not be circular. Square, hexagonal and
octagonal cross sections are effective scrambling geometries. The
output of the light pipe can directly couple to the input of the
tissue sampler or can be used in conjunction with additional
transfer optics before the light is sent to the tissue sampler.
See, e.g., U.S. patent application Ser. No. 09/832,586,
"Illumination Device and Method for Spectroscopic Analysis," which
is incorporated herein by reference.
[0169] In an example embodiment, the radiation homogenizer is a
light pipe. FIG. 29 shows a perspective end view and a detail plan
view of a light pipe of the present invention. Light pipe is
generally fabricated from a metallic, glass (amorphous),
crystalline, polymeric, or other similar material, or any
combination thereof. Physically, the light pipe comprises a
proximal end, a distal end, and a length therebetween. The length
of a light pipe, for this application, is measured by drawing a
straight line from the proximal end to the distal end of the light
pipe. Thus, the same segment of light pipe may have varying lengths
depending upon the shape the segment forms. The length of the
segment readily varies with the light pipe's intended
application.
[0170] In an example embodiment as illustrated in FIG. 29, the
segment forms an S-shaped light pipe. The S-shaped bend in the
light pipe provides angular homogenization of the light as it
passes through the light pipe. It is, however, recognized that
angular homogenization can be achieved in other ways. A plurality
of bends or a non-S-shaped bend could be used. Further, a straight
light pipe could be used provided the interior surface of the light
pipe included a diffusely reflective coating over at least a
portion of the length. The coating provides angular homogenization
as the light travels through the pipe. Alternatively, the interior
surface of the light pipe can be modified to include dimples or
"microstructures" such as micro-optical diffusers or lenses to
accomplish angular homogenization. Finally, a ground glass diffuser
could be used to provide some angular homogenization.
[0171] The cross-section of the light pipe may also form various
shapes. In particular, the cross-section of the light pipe is
preferably polygonal in shape to provide spatial homogenization.
Polygonal cross-sections include all polygonal forms having three
to many sides. Certain polygonal cross-sections are proven to
improve spatial homogenization of channeled radiation. For example,
a light pipe possessing a hexagonal cross-section the entire length
thereof provided improved spatial homogenization when compared to a
light pipe with a cylindrical cross-section of the same length.
[0172] Additionally, cross-sections throughout the length of the
light pipe may vary. As such, the shape and diameter of any
cross-section at one point along the length of the light pipe may
vary with a second cross-section taken at a second point along the
same segment of pipe. In certain embodiments, the light pipe is of
a hollow construction between the two ends. In these embodiments,
at least one lumen or conduit may run the length of the light pipe.
The lumens of hollow light pipes generally possess a reflective
characteristic. This reflective characteristic aids in channeling
radiation through the length of the light pipe so that the
radiation may be emitted at the pipe's distal end. The inner
diameter of the lumen may further possess either a smooth, diffuse
or a textured surface. The surface characteristics of the
reflective lumen or conduit aid in spatially and angularly
homogenizing radiation as it passes through the length of the light
pipe.
[0173] In additional embodiments, the light pipe is of solid
construction. The solid core could be cover plated, coated, or
clad. Again, a solid construction light pipe generally provides for
internal reflection. This internal reflection allows radiation
entering the proximal end of the solid light pipe to be channeled
through the length of the pipe. The channeled radiation may then be
emitted out of the distal end of the pipe without significant loss
of radiation intensity. An illustration of internal reflection and
the resulting channeling is shown in FIG. 30.
[0174] The faceted elliptical reflector is an example of an
embodiment of the present invention which produces only part of the
desired characteristics in the output radiation. In the case of the
faceted reflector, spatial homogenization is achieved but not
angular homogenization. In other cases, such as passing the output
of the standard system through ground glass, angular homogenization
is achieved but not spatial homogenization. In embodiments such as
these, where only angular or spatial homogenization is produced
(but not both) some improvement in the performance of the
spectroscopic system may be expected. However, the degree of
improvement would not be expected to be as great as for systems
where spatial and angular homogenization of the radiation are
simultaneously achieved.
[0175] Another method for creating both angular and spatial
homogenization is to use an integrating sphere in the illumination
system. Although common to use an integrating sphere for detection
of light, especially from samples that scatter light, integrating
spheres have not been used as part of the illumination system when
seeking to measure analytes noninvasively. In practice, radiation
output from the emitter could be coupled into the integrating
sphere with subsequent illumination of the tissue through an exit
port. The emitter could also be located in the integrating sphere.
An integrating sphere will result in exceptional angular and
spatial homogenization but the efficiency of this system is
significantly less than other embodiments previously specified.
[0176] It is also recognized that other modifications can be made
to the present disclosed system to accomplish desired
homogenization of light. For example, the light source could be
placed inside the light pipe in a sealed arrangement which would
eliminate the need for the reflector. Further, the light pipe could
be replaced by an integrator, wherein the source is placed within
the integrator. Further, the present system could be used in
non-infrared applications to achieve similar results in different
wavelength regions depending upon the type of analysis to be
conducted.
DESCRIPTION OF EXAMPLE EMBODIMENTS
[0177] In an example embodiment of the present invention
(schematically depicted in FIG. 31), a noninvasive alcohol
measurement system is comprised of 13 VCSEL's that are used to
measure 22 discrete wavelengths. Table 1 shows a list of each VCSEL
and the associated target peak wavelengths that will be
interrogated during the course of the measurement. In this
embodiment, each VCSEL is stabilized to a constant temperature. The
peak wavelength of each VCSEL is controlled based on the circuit
shown in FIG. 7 (each VCSEL having its own circuit), which also
enables the VCSEL to be turned On and Off. The specific state
(On/Off) of each VCSEL at a given time during a measurement is
determined by a predetermined Hadamard matrix. In example
embodiments incorporating solid state light sources the Hadamard
matrix is a pattern of On/Off states versus time for each VCSEL
that is stored in software rather than a physical mask or chopper.
This allows the On/Off states stored in software to be conveyed to
the electronic control circuits of each VCSEL during the
measurement.
TABLE-US-00001 TABLE 1 Light Source # Wavelengths measured
(cm.sup.-1) 1 4196.35, 4227.2 2 4288.91, 4304.34 3 4319.77, 4335.20
4 4350.62 5 4381.48, 4412.34 6 4443.19, 4474.05 7 4535.76, 4566.61
8 4597.47, 4612.90 9 4643.75 10 4674.61, 4690.04 11 4764.17 12
4828.88 13 4875.17, 4906.02
[0178] As several of the VCSEL's in table 1 are responsible for 2
wavelength locations, a Hadamard scheme that incorporates all
wavelengths can be difficult to achieve. In this case, a
combination of scanning and Hadamard encoding can allow all target
wavelengths to be measured. In the present embodiment, all VCSEL's
are tuned to their 1.sup.st target wavelength (for those with more
than 1 target wavelength) and a Hadamard encoding scheme used to
achieve the associated multiplex benefit. The VCSEL's can then be
tuned to their second target wavelength and a 2.sup.nd Hadamard
encoding scheme used. VCSEL's with only 1 target wavelength can be
measured in either or both groups or divided among the groups.
[0179] Furthermore, the groups can be interleaved in time. For
example, for a 2 second measurement, the first group can be
measured for the 1.sup.st second and the 2.sup.nd group for the
2.sup.nd second. Alternatively, the measurement can alternate at
0.5 second intervals for 2 seconds. The measurement times do not
need to be symmetric across the groups. For example, it can be
desirable to optimize signal to noise ratio by weighting the
measurement time towards one or the other group. One skilled in the
art recognizes that many permutations of measurement time,
balancing the number of groups, balancing the ratio of scanning to
Hadamard, and interleaving are possible and contemplated in the
embodiments of the present invention.
[0180] In the example embodiment, the output of each VCSEL is
combined and homogenized using a hexagonal cross-sectioned light
pipe. In some embodiments, the light pipe can contain one or more
bends in order to provide angular homogenization in addition to
spatial homogenization. Regardless, at the output of the light
pipe, the emission of all VCSEL's is preferably spatially and
angularly homogenized such that all wavelengths have substantially
equivalent spatial and angular content upon introduction to the
input of the sampling subsystem 200.
[0181] The homogenized light is introduced to the input of an
optical probe. In the example embodiment, the input is comprised of
225, 0.37 NA silica-silica optical fibers (referred to as
illumination fibers) arranged in a geometry consistent with the
cross section of the light homogenizer. The light is then
transferred to the sample interface. The light exits the optical
probe and enters the sample, a portion of that light interacts with
the sample and is collected by 64 collection fibers. In the present
example embodiment, the collection fibers are 0.37 NA silica-silica
fibers. FIG. 32 shows the spatial relationship between the
illumination and collection fibers at the sample interface.
[0182] The optical probe output arranges the collection fibers into
a geometry consistent with the introduction to a homogenizer. For
the example embodiment, the homogenizer is a hexagonal light pipe.
The homogenizer ensures that the content of each collection fiber
contributes substantially equally to the measured optical signal.
This can be important for samples, such as human tissue, that can
be heterogeneous in nature. The output of the homogenizer is then
focused onto an optical detector. In the present example
embodiment, the optical detector is an extended InGaAs diode whose
output current varies based upon the amount of incident light.
[0183] The processing subsystem then filters and processes the
current and then converts it to a digital signal using a 2 channel
delta-sigma ADC. In the example embodiment, the processed analog
detector signal is divided and introduced to both ADC channels. As
the example embodiment involves VCSEL's with 2 measurement groups
(e.g. 2 target wavelengths), a Hadamard transform is applied to the
spectroscopic signal obtained from each group and the subsequent
transforms combined to form an intensity spectrum. The intensity
spectrum is then base 10 log transformed prior to subsequent
alcohol concentration determination.
[0184] The example embodiment is suitable for either "enrolled" or
"walk-up/universal" modalities as well as applications combining
alcohol with other analyte properties such as substances of abuse.
Furthermore, any of the discussed modalities or combinations can be
considered independently or combined with the measurement of a
biometric property.
[0185] 3,245 alcohol measurements were obtained from 89 people on 5
noninvasive alcohol systems that measured spectra incorporating 22
wavelengths in the "walk-up" modality. The measurements spanned a
wide range of demographic and environmental. FIG. 33 shows the
near-infrared spectroscopic measurements obtained from the study.
FIG. 34 compares noninvasive alcohol concentrations obtained from
the spectroscopic measurements shown in FIG. 33 to contemporaneous
capillary blood alcohol concentration (BAC) alcohol.
[0186] In another example embodiment, 50 wavelengths are measured
using 24 VCSELs. Table 2 shows the VCSEL's and their target
wavelengths. As some of the VCSEL's contain 3 target wavelengths,
there are 3 groups, each with its own Hadamard encoding scheme. The
remainder of the system parameters, including the optical probe
design, light homogenizers, detector, and processing is identical
to the earlier described example embodiment.
TABLE-US-00002 TABLE 2 Light Source # Wavelengths measured
(cm.sup.-1) 1 4150.06 2 4227.20 3 4304.34, 4319.77, 4335.20 4
4350.62, 4366.05, 4381.48 5 4396.91, 4412.34, 4427.76 6 4443.19,
4458.62 7 4535.76 8 4566.61, 4582.04 9 4674.61, 4690.04, 4705.46 10
4751.75, 4767.17 11 4782.60, 4798.03 12 4890.60, 4906.02 13
5291.72, 5322.57 14 5384.28 15 5461.42, 5476.85 16 5708.27, 5723.69
17 5800.83, 5816.26 18 5847.12, 5862.54, 5877.97 19 5893.40,
5908.83 20 5939.68, 5955.11, 5970.54 21 6016.82, 6032.25 22 6063.10
23 6124.82, 6140.24 24 7189.33, 7204.76
[0187] In some example embodiments, calibration transfer can be
performed using a small number of measurements on samples with
known analyte properties. In the case of noninvasive alcohol
measurements, each instrument can have a small number of
measurements performed on individuals with no alcohol present. Any
non-zero alcohol result on the instrument translates into a
measurement error that can be used to correct subsequent
measurements on that instrument. The number of measurements used to
estimate the correction can vary and generally depends on the
required accuracy of the correction. In general, this process is
analogous to an instrument specific calibration consistent with
alcohol devices, such as breath testers, that are calibrated
individually.
[0188] A similar approach can be applied to calibration
maintenance. In many applications of alcohol testing, the majority
of measurements are performed on individuals where alcohol is
unlikely to be present. For example in workplace safety where
employees are routinely tested for alcohol, it is much more likely
that an employee will be alcohol free than intoxicated (e.g. most
people enter the workplace alcohol-free). In this case, the true
alcohol concentration can be assumed to be zero and a median or
other means for excluding the infrequent, true alcohol events could
be used to estimate an instruments correction. This can implemented
as a running median filter, a moving window, or more sophisticated
multivariate algorithm for determining the appropriate correction
at a given time.
[0189] Those skilled in the art will recognize that the present
invention can be manifested in a variety of forms other than the
specific embodiments described and contemplated herein.
Accordingly, departures in form and detail can be made without
departing from the scope and spirit of the present invention as
described in the appended claims.
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