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`c19) United States
`
`
`c12) Patent Application Publication
`c10) Pub. No.: US 2011/0282167 Al
`
`(43) Pub. Date: Nov. 17, 2011
`Ridder et al.
`
`US 20110282167Al
`
`
`
`Publication Classification
`
`(54) SYSTEM FOR NONINVASIVE
`
`
`DETERMINATION OF ALCOHOL IN TISSUE
`(51)Int. Cl.
`A61B 511455(2006.01)
`
`
`
`(76) Inventors: Trent Ridder, Woodbridge, VA
`
`
`
`
`
`(US); Ben Ver Steeg, Redlands, CA
`
`
`
`(US); Mike Mills, Tijeras, NM
`
`(US); Bentley Laaksonen,
`
`Albuquerque, NM (US)
`
`(52)U.S. Cl. ........................................................ 600/322
`
`(57)
`
`ABSTRACT
`
`An apparatus and method for non-invasive determination of
`
`
`
`
`
`
`attributes of human tissue by quantitative infrared spectros­
`
`
`
`copy to clinically relevant levels of precision and accuracy.
`
`
`
`
`The system includes subsystems optimized to contend with
`
`
`
`
`the complexities of the tissue spectrum, high sign al-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 cali­
`
`
`
`bration maintenance subsystem, an FTIR spectrometer sub­
`
`
`
`system, a data acquisition subsystem, and a computing
`
`Provisional application No. 61/147,107, filed on Jan.
`subsystem.
`
`
`
`(21) Appl. No.: 13/145,927
`
`
`
`(22) PCT Filed: Jan.23,2010
`
`
`
`(86) PCT No.: PCT/USl0/21898
`
`§371 (c)(l),
`
`(2), ( 4) Date:Jul. 22, 2011
`
`
`
`
`
`Related U.S. Application Data
`
`(60)
`
`
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`SYSTEM FOR NONINVASIVE
`DETERMINATION OF ALCOHOL IN TISSUE
`
`FIELD OF THE INVENTION
`0001. The present invention generally relates to a quanti
`tative spectroscopy system for measuring the presence or
`concentration of alcohol, alcohol byproducts, alcohol
`adducts, or Substances of abuse utilizing non-invasive tech
`niques 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 alco
`hol intoxication levels. However, blood measurements
`require either a venous or capillary sample and involve sig
`nificant 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 suit
`able location where a clinical gas chromatograph is typically
`used to measure the blood alcohol level. Due to the invasive
`ness 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 mea
`sures 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 applica
`tions, 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 parti
`tion 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 gen
`eral, seek non-invasive alternatives to blood and breath alco
`hol measurements. Quantitative spectroscopy offers the
`potential for a completely non-invasive alcohol measurement
`that is not sensitive to the limitations of the current measure
`ment 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, ana
`lyte presence, analyte concentration (e.g., alcohol concentra
`tion), 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 spec
`troscopy are desirable because they are painless, do not
`require a fluid draw from the body, carry little risk of con
`tamination 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 spectros
`copy, Kromoscopy, fluorescence spectroscopy, nuclear mag
`netic resonance spectroscopy, radio-frequency spectroscopy,
`ultrasound, transdermal measurements, photo-acoustic spec
`troscopy, 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 concentra
`tion of an analyte, such as alcohol, but also can be any chemi
`cal or physical property of the sample. The method of Rob
`inson 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 calibra
`tion model. The model preferably accounts for subject vari
`ability, 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 pre
`diction step is the estimated value of the characteristic of the
`unknown sample. The disclosure of Robinson et al. is incor
`porated 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.
`
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`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 spectrom
`eters, 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 formi
`dable task. Thus, there is a substantial need for a commer
`cially viable device which incorporates subsystems and
`methods with Sufficient accuracy and precision to make clini
`cally relevant determinations of biological attributes in
`human tissue.
`
`SUMMARY OF THE INVENTION
`0013 The present invention generally relates to a quanti
`tative spectroscopy system for measuring the presence or
`concentration of alcohol, alcohol byproducts, alcohol
`adducts, or substances of abuse utilizing non-invasive tech
`niques 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 illumi
`nation/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 determi
`nation of the attribute by quantitative near-infrared spectros
`copy.
`0016. The present invention can use near-infrared radia
`tion for analysis. Radiation in the wavelength range of 1.0 to
`2.5 microns (or wavenumber range of 10,000 to 4,000 cm)
`can be suitable for making some non-invasive measurements
`because Such radiation has acceptable specificity for a num
`ber 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 measure
`ments of the substance of interest can beachieved. Multivari
`ate analysis techniques, however, can require that multivari
`ate calibrations remain robust over time (calibration
`maintenance) and be applicable to multiple instruments (cali
`bration transfer). Other wavelength regions, such as the vis
`ible and infrared, can also be suitable for the present inven
`tion.
`0017. The present invention documents a multidisci
`plinary approach to the design of a spectroscopic instrument
`that incorporates an understanding of the instrument Sub
`systems, tissue physiology, multivariate analysis, near-infra
`red 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-inva
`sive measurements with Sufficient accuracy and precisionata
`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 trans
`fer, 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 homog
`enizing 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;
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`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 appa
`ratus 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 sam
`pling Surface of the tissue sampling Subsystem;
`0032 FIG. 14 is an alternative embodiment of the sam
`pling 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 sam
`pling 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 posi
`tioning 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 forma
`tion process;
`0042 FIG. 24 is a schematic representation of a decision
`process that combines three topical interferent mitigation
`Strategies:
`0.043
`FIG.25 demonstrates the effectiveness of multivari
`ate 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 (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 sev
`eral demonstrative NIR LED's:
`0047 FIG. 29 is a perspective end view and a detail plan
`view of a lightpipe suitable for use with the present invention;
`0.048
`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 illumi
`nation and collection fibers at the sample interface for an
`example embodiment of an optical probe of the present inven
`tion;
`0051 FIG.33 depicts noninvasive tissue spectra acquired
`using 22 wavelengths;
`0052 FIG. 34 compares noninvasive tissue alcohol con
`centrations obtained from the spectra in FIG. 33 to contem
`poraneous 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 Vol
`ume (MCV), Carbohydrate-Deficient Transferrin (CDT),
`Ethyl Glucuronide (EtG), Ethyl Sulfate (EtS), and Phosphati
`dyl Ethanol (PEth). The term “substances of abuse' refers to,
`but is not limited to, THC (Tetrahydrocannabinol or mari
`juana), cocaine, M-AMP (methamphetamine), OPI (mor
`phine and heroin), OxyContin, Oxycodone, and PCP (phen
`cyclidine). 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 inven
`tion 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 “semiconduc
`tor light source” refer to all sources of light, whether spec
`trally 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 emit
`ting 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 LEDs, 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 “disper
`sive spectrometer indicates a spectrometer based upon any
`device, component, or group of components that spatially
`separate one or more wavelengths of light from other wave
`lengths. Examples include, but are not limited to, spectrom
`eters that use one or more diffraction gratings, prisms, holo
`graphic gratings. For the purposes of this invention the term
`“interferometric/modulating spectrometer indicates a class
`of spectrometers based upon the optical modulation of differ
`ent 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 interferom
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`eters, Sagnac interferometers, mock interferometers, Mich
`elson interferometers, one or more etalons, or acousto-optical
`tunable filters (AOTFs). One skilled in the art recognizes that
`spectrometers based on combinations of dispersive and inter
`ferometric/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 regres
`Sion, 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 spe
`cial 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 interferom
`eter) spectrometers. Noninvasive measurement systems that
`incorporate such approaches are often limited by the expen
`sive nature of dis