System and method for non-invasively measuring material to be analyzed in automobile driver

Abstract

To provide a system and a method for non-invasively measuring a material to be analyzed in an automobile driver.SOLUTION: There is provided a system for non-invasively measuring a material to be analyzed in an automobile driver and controlling an automobile based on a measurement value of the material to be analyzed. At least one solid light source is configured to emit light of different wavelengths. A sample device is configured to introduce the light emitted by the at least one solid light source to a tissue of the automobile driver. One or more light detectors are configured to detect part of the light that is not absorbed by the tissue of the automobile driver. A controller is configured to calculate a measurement value of the material to be analyzed in the tissue of the automobile driver based on the light detected by the one or more light detectors, determine whether or not the measurement value of the material to be analyzed in the tissue of the automobile driver exceeds a predetermined value, and provide a signal to a device configured so as to control the automobile.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] (Citation of related patent application) This application claims priority from U.S. Provisional Application No. 61 / 528,658, filed Aug. 29, 2011, the entirety of which is incorporated herein by reference.

[0002] This application relates generally to systems and methods for non-invasively measuring analytes in motor vehicle drivers. More specifically, this application relates to a quantitative spectroscopic system for measuring the presence or concentration of an analyte, such as alcohol, alcohol by-products, alcohol adducts, or substances of abuse, utilizing non-invasive techniques in combination with multivariate analysis. [Background technology]

[0003] Current practice for alcohol measurement is based on either blood measurement or breath testing. Blood measurement defines the criteria for determining alcoholism levels. However, blood measurement requires either venous or capillary samples and involves significant handling precautions to minimize health risks. Once drawn, 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 invasive nature of the procedure and the amount of sample handling involved, blood alcohol measurement is usually limited to critical situations such as traffic accidents, violations where suspects require this type of test, and accidents involving injuries.

[0004] Breath testing is more commonly encountered in the field because it is less invasive. In a breath test, the subject must exhale air into the device for a sufficient time and volume to achieve a steady breath flow originating from the alveoli deep within the lungs. The device then measures the alcohol content in the air, which is related to blood alcohol through the breath-blood partition coefficient. The breath-blood 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 countries. The variability of 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 range of 1900 to 2400 that depends on his or her physiology. Because knowledge of the partition coefficient of each subject is not available in field applications, each country assumes a single partition coefficient value that is globally applied to all measurements. In the United States, defendants in drunk driving cases often use the globally applied partition coefficient as an argument to bar prosecution.

[0005] Breath measurements have additional limitations. First, the presence of "oral alcohol" can falsely elevate the breath alcohol measurement. This necessitates a 15-minute wait period before taking a measurement to ensure that no oral alcohol is present. For similar reasons, a 15-minute delay is required for individuals who are observed to burp or vomit. Often, a delay of 10 minutes or more is required between breath measurements to allow the equipment to return to equilibrium with the ambient air and zero alcohol levels. In addition, the accuracy of breath alcohol measurements is sensitive to a number of physiological and environmental factors.

[0006] Multiple governmental agencies and society at large are seeking non-invasive alternatives to blood and breath alcohol measurement. Quantitative spectroscopy offers the potential for completely non-invasive alcohol measurement that is not sensitive to the limitations of current measurement methodologies. Non-invasive determination of biological attributes by quantitative spectroscopy has proven highly desirable, yet extremely difficult to achieve. Attributes of interest include, by way of example, the presence of an analyte, the concentration of an analyte (e.g., alcohol concentration), the direction of change of the analyte concentration, the rate of change of the analyte concentration, the presence of a disease (e.g., alcoholism), a medical condition, and combinations and subsets thereof. Non-invasive measurement via quantitative spectroscopy is desirable because it is painless, does not require fluid withdrawal from the body, poses little risk of contamination or infection, does not generate any hazardous waste, and can have a short measurement time.

[0007] Several systems have been proposed for the non-invasive determination of biological tissue attributes. These systems have included techniques incorporating polarimetry, mid-infrared spectroscopy, Raman spectroscopy, chromometry, fluorescence spectroscopy, nuclear magnetic resonance spectroscopy, radio spectroscopy, ultrasound, transcutaneous measurements, photoacoustic spectroscopy, and near-infrared spectroscopy. However, these systems have not replaced direct, invasive measurements.

[0008] As an example, Robinson et al. in U.S. Patent No. 5,399,633 disclose a method and apparatus for measuring a property of unknown value in a biological sample using infrared spectroscopy in conjunction with a multivariate model empirically derived from a wide variety of biological samples with a set of known characteristic values. The property is generally the concentration of an analyte such as alcohol, but can be any chemical or physical property of the sample. The Robinson et al. method involves a two-step process that includes both a calibration and a prediction step.

[0009] In the calibration step, infrared light is coupled into calibration samples of known property values ​​such that there is attenuation of at least some wavelengths of infrared radiation as a function of the various components and analytes comprising the samples with known property values. The infrared light is coupled into the samples by passing the light through the samples or by reflecting the light from the samples. Absorption of the infrared light by the samples causes intensity variations of the light that are a function of the wavelength of the light. The resulting intensity variations at a minimum of some wavelengths are measured for a set of calibration samples of known property values. The original or transformed intensity variations are then empirically related to the known properties of the calibration samples using a multivariate algorithm to obtain a multivariate calibration model. The model preferably takes into account subject variability, instrument variability, and environmental variability.

[0010] In the prediction step, infrared light is coupled to a sample of unknown property values, and the multivariate calibration model is applied to the original or transformed intensity variations of the appropriate wavelengths of light measured from the unknown sample. The result of the prediction step is an estimate of the property of the unknown sample. The disclosure of Robinson et al. is incorporated herein by reference.

[0011] Further methods of constructing calibration models and using the models to predict analyte and / or tissue attributes are disclosed in commonly assigned U.S. Patent No. 6,233,336 to Thomas et al., entitled "Method and Apparatus for Tailoring Spectrographic Calibration Models," the disclosure of which is incorporated herein by reference.

[0012] In US Patent No. 5,399,633, Robinson describes a general method for robust sampling of tissue for non-invasive analyte measurement. The sampling method utilizes a tissue sampling appendage whose path length is optimized by the spectral region for measuring an analyte such as alcohol. The patent discloses several types of spectrometers for measuring the spectrum of tissue from 400 to 2500 nm, including acousto-optic tunable filters, discrete wavelength spectrometers, filters, grating spectrometers, and FTIR spectrometers. The disclosure of Robinson is incorporated herein by reference. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] U.S. Pat. No. 4,975,581 [Patent Document 2] U.S. Patent No. 6,157,041 [Patent Document 3] U.S. Patent No. 5,830,112 Summary of the Invention [Problem to be solved by the invention]

[0014] Although a great deal of research has been conducted in an attempt to produce a commercially viable non-invasive near-infrared spectroscopy-based system for the determination of biological attributes, no such device is currently available. It is believed that the prior art systems discussed above, for one or more reasons, have failed to fully address the challenges posed by the spectral characteristics of tissue, which make the design of a non-invasive measurement system a formidable task. Thus, there is a great need for a commercially viable device that incorporates subsystems and methods with sufficient accuracy and precision to perform clinically relevant determinations of biological attributes in human tissue. [Means for solving the problem]

[0015] One embodiment of the present invention relates to a system for non-invasively measuring an analyte in a motor vehicle driver and controlling the motor vehicle based on the analyte measurements. The system includes at least one solid-state light source, a sample device, one or more photodetectors, and a controller. The at least one solid-state light source is configured to emit different wavelengths of light. The sample device is configured to introduce light emitted by the at least one solid-state light source into a tissue of the motor vehicle driver. The one or more photodetectors are configured to detect a portion of the light that is not absorbed by the tissue of the motor vehicle driver. The controller is configured to calculate a measurement of the analyte in the tissue of the motor vehicle driver based on the light detected by the one or more photodetectors, determine whether the measurement of the analyte in the tissue of the motor vehicle driver exceeds a predetermined value, and provide a signal to a device configured to control the motor vehicle.

[0016] Another embodiment of the invention relates to a method for non-invasively measuring an analyte in a motor vehicle driver and controlling the motor vehicle based on the analyte measurements. A sample device introduces different wavelengths of light emitted by at least one solid-state light source into the motor vehicle driver's tissue. One or more photodetectors detect a portion of the light that is not absorbed by the motor vehicle driver's tissue. A controller calculates a measurement of the analyte in the motor vehicle driver's tissue based on the light detected by the one or more photodetectors. The controller determines whether the measurement of the analyte in the motor vehicle driver's tissue exceeds a predetermined value and controls the motor vehicle based on the measurement of the analyte in the motor vehicle driver's tissue.

[0017] Additional features, advantages, and embodiments of the present disclosure may be described from consideration of the following detailed description, drawings, and claims. It should also be understood that both the foregoing summary of the disclosure and the following detailed description are exemplary and intended to provide further explanation without further limiting the scope of the disclosure as claimed. For example, the present invention provides the following items: (Item 1) 1. A system for non-invasively measuring an analyte in a vehicle driver and controlling the vehicle based on the analyte measurements, comprising: at least one solid state light source configured to emit different wavelengths of light; a sample device configured to introduce the light emitted by the at least one solid-state light source into a tissue of the motor vehicle operator; and one or more photodetectors configured to detect a portion of the light that is not absorbed by the tissues of the vehicle operator; and a controller configured to calculate a measurement of the analyte in the tissue of the vehicle driver based on the light detected by the one or more optical detectors, determine whether the measurement of the analyte in the tissue of the vehicle driver exceeds a predetermined value, and provide a signal to a device configured to control the vehicle; A system comprising: (Item 2) Item 1. The system of item 1, further comprising a biometric device configured to identify or verify the identity of the vehicle operator. (Item 3) The system of item 2, wherein the biometric device collects a set of biometric data from the motor vehicle operator and compares the set of biometric data with a set of enrollment data corresponding to authorized motor vehicle operators stored in the biometric device to identify, if applicable, which of the authorized motor vehicle operators provided the set of biometric data. (Item 4) 3. The system of claim 2, wherein a predicted vehicle driver provides an intended identity to the vehicle, the biometric device collects a set of biometric data from the predicted vehicle driver, and the biometric device verifies whether the actual identity of the predicted vehicle driver is the intended identity of the predicted vehicle driver by comparing the set of biometric data of the predicted vehicle driver to the set of enrollment data corresponding to the intended identity of the predicted vehicle driver. (Item 5) Item 2. The system of item 1, wherein the intensity of each solid-state light source is configured to be independently modulated. (Item 6) Item 6. The system of item 5, wherein the light emitted from each solid-state light source is configured to be combined into a single beam such that the light emitted from each solid-state light source is always introduced into and collected from the tissue of the vehicle operator. (Item 7) 7. The system of claim 6, wherein the light emitted from the at least one solid-state light source and detected by the one or more photodetectors has a wavelength between 1,000 nm and 2,500 nm. (Item 8) Item 14. The system of item 1, further comprising a microcontroller configured to turn the at least one solid-state light source on and off according to a set of states defined by a predetermined modulation scheme. (Item 9) 2. The system of claim 1, wherein each solid-state light source is configured to be tuned to multiple peak wavelength locations such that the system is capable of measuring more wavelength locations than the number of solid-state light sources provided in the system. (Item 10) Item 10. The system of item 1, further comprising a light homogenizer configured to provide a uniform radiance of the light introduced by the sample device into the tissue of the motor vehicle operator. (Item 11) 2. The system of claim 1, wherein the measurement of the analyte comprises a presence, a concentration, a rate of change of the concentration, a direction of change of the concentration, or a combination thereof of the analyte. (Item 12) 2. The system of claim 1, wherein the measurements of the analytes are obtained using multivariate analysis. (Item 13) Item 2. The system of item 1, wherein a plurality of solid-state light sources are arranged in a planar array. (Item 14) 2. The system of claim 1, wherein the plurality of solid-state light sources are divided into one or more groups, and each solid-state light source in the one or more groups is mounted on a common carrier for each group with a predefined spacing between other solid-state light sources mounted on the same common carrier. (Item 15) Item 2. The system of item 1, wherein the multiple solid-state light sources are arranged such that the multiple solid-state light sources are located within a single semiconductor to form a laser bar. (Item 16) Item 2. The system of item 1, wherein the laser bar comprises one or more groups of solid state light sources, each group of solid state light sources having the same wavelength that is different from the wavelength of an adjacent group of solid state light sources. (Item 17) 2. The system of claim 1, wherein the system is configured to measure more than one analyte. (Item 18) 1. A method for non-invasively measuring an analyte in a vehicle driver and controlling the vehicle based on the analyte measurements, comprising: introducing, by a sample device, different wavelengths of light emitted by at least one solid-state light source into tissue of the motor vehicle operator; detecting, with one or more photodetectors, a portion of the light that is not absorbed by the tissues of the vehicle operator; calculating, by a controller, a measurement of the analyte in the tissue of the vehicle operator based on the light detected by the one or more light detectors; determining, by the controller, whether the measured value of the analyte in the tissue of the vehicle operator exceeds a predetermined value; controlling the vehicle based on the measurements of the analytes in the tissues of the vehicle operator; A method comprising: (Item 19) collecting, by a biometric device, a set of biometric data to identify the motor vehicle operator; comparing, by the biometric device, the set of biometric data with a set of enrollment data corresponding to authorized motor vehicle operators previously stored in the biometric device; If applicable, identifying which of said authorized motor vehicle operators provided said set of biometric data; 20. The method of claim 18, further comprising: (Item 20) providing, by a predicted vehicle operator, an intended identity to said vehicle; collecting, by said biometric device, a set of biometric data from said prospective vehicle operator; comparing, by the biometric device, the set of biometric data with the set of enrolment data corresponding to the intended identity of the prospective motor vehicle operator; verifying, by the biometric device, whether an actual identity of the predicted vehicle driver is the intended identity of the predicted vehicle driver based on the comparison; 20. The method of claim 18, further comprising: (Item 21) 20. The method of claim 18, wherein the intensity of each solid-state light source is independently modulated. (Item 22) Item 19. The method of item 18, further comprising turning on and off, by a microcontroller, the at least one solid-state light source according to a set of states defined by a predetermined modulation scheme. (Item 23) 20. The method of claim 18, wherein the measurement of the analyte comprises the presence, concentration, rate of change of the concentration, direction of change of the concentration of the analyte, or a combination thereof. (Item 24) 20. The method of claim 18, wherein the measurements of the analytes are obtained using multivariate analysis. (Item 25) 20. The method of claim 18, further comprising measuring more than one analyte. [Brief description of the drawings]

[0018] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate preferred embodiments of the invention and, together with the description, serve to explain the principles of the invention. No attempt is made to show structural details of the disclosure in more detail than may be necessary for a fundamental understanding of the disclosure and various ways in which it may be practiced. [Figure 1] FIG. 1 is a schematic diagram of a non-invasive spectrometer system incorporating the disclosed subsystems. [Diagram 2] Figure 2 is a schematic depiction of the concept of net attribute signals within a three-component system. [Diagram 3] FIG. 3 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. [Figure 4] FIG. 4 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 varying the desired drive current. [Diagram 5] FIG. 5 is an embodiment of an illumination / modulation subsystem comprising multiple individual solid-state light sources arranged in an array whose output is introduced into a hexagonal cross-section internal reflection type light homogenizer. [Figure 6] FIG. 6 is an embodiment of a single laser emitter in a semiconductor chip. [Figure 7] FIG. 7 is an embodiment of an illumination / modulation subsystem in which multiple laser emitters are mounted on a common carrier. [Figure 8] FIG. 8 is an embodiment of an illumination / modulation subsystem depicting a laser bar consisting of a single semiconductor chip containing 24 emitters (12 different wavelengths, two emitters per wavelength). [Figure 9] FIG. 9 is a schematic diagram of an embodiment of a fiber optic coupler that collects the light emitted from each pair of emitters in the laser bar embodiment shown in FIG. 8 and incorporates individual optical fibers into an output bundle or cable. [Figure 10]FIG. 10 is an embodiment that combines the outputs of four different fiber couplers into a single output aperture / bundle, with each coupler connected to a different laser bar. [Figure 11] FIG. 11 is an example embodiment of a light homogenizer suitable for homogenizing the light from the output aperture / bundle of the illumination / modulation subsystem. [Figure 12] FIG. 12 is a perspective view of elements of the tissue sampling subsystem. [Figure 13] FIG. 13 is a plan view of the sampling surface of the tissue sampling subsystem showing the arrangement of illumination and collection optical fibers. [Figure 14] FIG. 14 is an alternative embodiment of a sampling surface of the tissue sampling subsystem. [Figure 15] FIG. 15 is an alternative embodiment of a sampling surface of the tissue sampling subsystem. [Figure 16] FIG. 16 is an alternative embodiment of a sampling surface of a tissue sampling subsystem that is optimized for the small light emitting area of ​​some solid state light source based illumination / modulation subsystems. [Figure 17] FIG. 17 is a schematic representation of the interface between a sampling surface and tissue when a local interferent is present on the tissue. [Figure 18] FIG. 18 is a schematic diagram of the data acquisition subsystem. [Figure 19] FIG. 19 is a schematic diagram of the hybrid calibration formation process. [Figure 20] FIG. 20 demonstrates the effectiveness of the multivariate calibrated outlier metric for detecting the presence of local interferents. [Figure 21] FIG. 21 shows the normalized NIR spectrum of a 1300-3000 K blackbody radiator over the range 100-33000 cm (100-0.3 μm). [Figure 22] FIG. 22 is a schematic diagram of components of an exemplary embodiment of the present invention. [Figure 23] FIG. 23 depicts non-invasive tissue spectra collected using 22 wavelengths. [Figure 24]FIG. 24 compares the non-invasive tissue alcohol concentrations obtained from the spectra of FIG. 23 with the simultaneous capillary blood alcohol concentrations. [Diagram 25] FIG. 25 depicts the non-invasive tissue spectrum acquired using 39 wavelengths. [Figure 26] FIG. 26 compares the non-invasive tissue alcohol concentrations obtained from the spectra of FIG. 25 with the simultaneous capillary blood alcohol concentrations. [Figure 27] FIG. 27 depicts one of many possible embodiments of a measurement time series, including system calibration, measurement, and countermeasure windows. [Figure 28] FIG. 28 depicts a non-invasive monitoring system integrated into an automobile instrument panel as an automobile start button. [Figure 29a] FIG. 29a depicts a side view of a non-invasive measurement portal interface in which the emitter is a wavelength homogenizer directly connected to a wavelength light source. [Figure 29b] FIG. 29b depicts a top view of the non-invasive measurement portal interface of FIG. 29a, where the emitter is a wavelength homogenizer directly connected to a wavelength light source. [Diagram 30] FIG. 30 depicts components of a non-invasive monitoring system that utilizes a widely tunable laser emitter to provide a means for spectrally resolved absorption measurements. [Diagram 31] FIG. 31 depicts one of many possible embodiments of a measurement time sequence that improves the average required measurement time, where an initial measurement is taken to detect the presence of an analyte and subsequent measurements are taken to determine the actual concentration of the analyte. [Diagram 32] FIG. 32 depicts a non-invasive monitoring system in which a primary analyte measurement is made through a touch system and a secondary measurement is made through an alternative analyte detection system. [Diagram 33] FIG. 33 depicts components of a non-invasive monitoring system that utilizes a blackbody light source with filter elements to provide a selection of discrete wavelengths that constitute the emitted light source. [Diagram 34]FIG. 34 illustrates that a measurement of the intensity of the light source during the transition from the OFF state to the ON state is made prior to the intensity determination. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Before turning to the figures which illustrate the exemplary embodiments in detail, it is to be understood that the disclosure is not limited to the details or methodology set forth in the description or illustrated in the figures. It is also to be understood that the terminology is for descriptive purposes only and should not be regarded as limiting. An effort has been made to use the same or similar reference numbers throughout the figures to refer to the same or similar parts.

[0020] For purposes of this application, 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, the direction or rate of change of the analyte concentration, or a biometric, that can be measured in conjunction with or instead of the analyte concentration. Although this disclosure generally refers to alcohol as the "analyte" of interest, other analytes, including but not limited to substances of abuse, alcohol biomarkers, and alcohol by-products, are also intended to be contemplated by the systems and methods disclosed herein. The term "alcohol" is used as an example analyte of interest, and the term is intended to include ethanol, methanol, ethyl glycol, or any other chemical commonly referred to as alcohol. For purposes of this application, the term "alcohol by-products" includes adducts and by-products 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 glutamine transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), mean corpuscular volume (MCV), carbohydrate deficient transferrin (CDT), ethyl glucuronide (EtG), ethyl sulfate (EtS), and phosphatidylethanol (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 particular individual or subject. This application discloses systems and methods that utilize spectroscopy to address the need for analyte measurements of a sample, where the term "sample" generally refers to a biometric measurement. The term "subject" generally refers to an individual from whom a sample measurement is collected.

[0021] The term "solid-state light source" or "semiconductor light source" refers to all light sources, whether spectrally narrow (e.g., lasers) or broad (e.g., LEDs), that are based on semiconductors, including, but not limited to, light emitting diodes (LEDs), vertical-cavity surface-emitting lasers (VCSELs), horizontal-cavity surface-emitting lasers (HCSELs), quantum cascade lasers, quantum dot lasers, diode lasers, or other semiconductor diodes or lasers. The term "diode laser" refers to any laser in which the active medium is based on a semiconductor, including, but not limited to, double heterostructure lasers, quantum well lasers, quantum cascade lasers, separate confinement heterostructure lasers, distributed feedback (DFB) lasers, VCSELs, VECSELs, HCSELs, external cavity diode lasers, and Fabry-Perot lasers. Additionally, while not strictly semiconductor based, plasma light sources and organic LEDs are also contemplated in embodiments of the present invention, and thus are included under the definition of solid-state light source and semiconductor light source for purposes of this application.

[0022] For purposes of this application, the term "dispersive spectrometer" refers to a spectrometer based on any device, component, or group of components that spatially separates 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 purposes of this application, the term "interference / modulation spectrometer" refers to a type of spectrometer based on optical modulation of different wavelengths of light to different frequencies in time, or selectively transmit or reflect certain wavelengths of light based on optical interference properties. 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 (AOTFs). Those skilled in the art will recognize that spectrometers based on a combination of dispersive and interference / modulation properties, such as spectrometers based on lamellar gratings, are also considered for use with the systems and methods disclosed herein.

[0023] The present application discloses in some of the examples the use of a "signal" as an absorbance or other spectroscopic measurement. The signal can include any measurement obtained of a spectroscopic measurement of a sample or a change in a sample, such as absorbance at one or more wavelengths, reflectance, recovered light intensity, fluorescence, transmittance, Raman spectrum, or various combinations of measurements. Some embodiments utilize one or more models, and such models can be anything that relates the signal to a 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 component analysis (PCA), principal component 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 therefore included in the term multivariate analysis for purposes of this application.

[0024] For purposes of this application, the term "about" applies to all numerical values, whether or not expressly indicated. The term "about" generally refers to a series of numbers that one of ordinary skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In some cases, the term "about" can include numbers that are rounded to the nearest significant figure.

[0025] Spectroscopic measurement systems typically require some means to resolve and measure different wavelengths of light to obtain a spectrum. Some common approaches to achieve a desired spectrum include dispersive (e.g., grating and prism-based) spectrometers and interferometric (e.g., Michelson, Sagnac, or other interferometer) spectrometers. Non-invasive measurement systems incorporating such approaches are often limited by the expensive nature of dispersive and interferometric devices, as well as their inherent size, fragility, and susceptibility to environmental effects. This application discloses systems and methods that can provide an alternative approach to resolve and record the intensity of different wavelengths using solid-state light sources, such as light-emitting diodes (LEDs), vertical-cavity surface-emitting lasers (VCSELs), horizontal-cavity surface-emitting lasers (VCSELs), diode lasers, quantum cascade lasers, or other solid-state light sources.

[0026] Generally, with reference to the figures, the disclosed system overcomes the challenges posed by the spectral characteristics of tissue by incorporating a design that, in some embodiments, includes optimized subsystems that address the complexities of tissue spectra, high signal-to-noise ratio and photometric accuracy requirements, tissue sampling errors, calibration maintenance issues, calibration movement issues, and numerous other issues. The subsystems can include an illumination / modulation subsystem, a tissue sampling subsystem, a data acquisition subsystem, a computer subsystem, and a calibration subsystem.

[0027] Disclosed herein is an apparatus and method for non-invasive determination of attributes of human tissue by quantitative near-infrared spectroscopy. The system includes subsystems that are optimized to address the complexities of noise ratio and photometric accuracy requirements, tissue sampling errors, calibration maintenance issues, and calibration transfer issues. The subsystems include an illumination / modulation subsystem, a tissue sampling subsystem, a data acquisition subsystem, and a computer subsystem.

[0028] This application further discloses an apparatus and method that allows for the implementation and integration of each of these subsystems to maximize the net attribute signal-to-noise ratio. The net attribute signal is the portion of the near-infrared spectrum that is specific to the attribute of interest because it is orthogonal to all other sources of spectral dispersion. The orthogonality 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 with these sources of dispersion. The net attribute signal-to-noise ratio is directly related to the accuracy and precision of the non-invasive determination of an attribute by quantitative near-infrared spectroscopy.

[0029] This application discloses the use of near infrared radiation for analysis in the wavelength range of 1.0 to 2.5 microns (or 10,000 to 4,000 cm). -1 Radiation within the wavelength range of 1.0 to 2.5 microns (wavenumber range) may be suitable for making some non-invasive measurements because such radiation has acceptable specificity for some analytes, including alcohol, along with tissue optical penetration depths of up to several 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 tissue complicates the measurement of any given substance due to the overlapping nature of their absorbance spectra. Multivariate analytical techniques can be used to resolve these overlapping spectra so that accurate measurements of the substance of interest can be achieved. However, multivariate analytical techniques may require that the multivariate calibration remain robust over time (calibration maintenance) and be applicable to multiple instruments (calibration transfer). Other wavelength regions, such as visible light and infrared, may also be suitable for the disclosed systems and methods.

[0030] This application discloses a multidisciplinary approach to the design of a spectroscopic instrument that incorporates an understanding of instrument subsystems, tissue physiology, multivariate analysis, near infrared spectroscopy, and overall system operation. Furthermore, the behavior and requirements of the entire noninvasive measurement device are well understood, and the interactions between the subsystems have been analyzed to result in the design of a commercial instrument that will perform noninvasive measurements with sufficient accuracy and precision at a commercially feasible price and size.

[0031] The present application also discloses systems and methods for use with the unique sensing requirements of transportation systems, including but not limited to motorcycles, automobiles, trucks, ships, trains, and aircraft, where the system must operate across a wide range of environments of temperature, atmospheric pressure, altitude, humidity, mechanical orientation, ambient lighting, and environmental constituents (e.g., salt, sand, dust, smoke). The disclosed system may operate across a full range of potential users who are identifiable through differences in weight, height, age, race, sex, health, fitness level, and other human distinguishing factors. The disclosed system may remain functional throughout the life of the vehicle and maintain diagnostics and indicators indicating required maintenance or available unit replacement. The disclosed system may provide a human-machine interface that provides visual, tactile, and audible feedback to inform the system user of correct or incorrect measurements. The system provides diagnostics and user feedback indicating proper or improper measurements, including detection of intentional or unintentional system tampering or measurement spoofing. The system may maintain an operating model that can be enabled / disabled based on administrative control (e.g., password). The system may provide one or more communication and / or power interfaces to external transport enabling or human machine interface systems using one or more existing or developed communication protocols to receive data and / or power required for system operation or to enable, disable or modify operation of an external system. The system may support the ability to enable measurement accuracy and precision verification or calibration during manufacture, installation and / or service through prosthetic reference devices.

[0032] The noninvasive monitor subsystems are highly optimized to provide reproducible and preferably uniform radiance of tissue, low tissue sampling error, depth targeting of tissue layers containing properties of interest, efficient collection of diffuse reflectance spectra from tissue, high optical throughput, high photometric accuracy, wide dynamic range, excellent thermal stability, effective calibration maintenance, effective calibration transfer, built-in quality control, and ease of use.

[0033] Referring now to Figure 1, a non-invasive monitor capable of achieving an acceptable level of accuracy and precision of analyte property measurements is depicted in a schematic diagram. The overall system can be viewed, for discussion purposes, as comprising five subsystems. Those skilled in the art will appreciate other subdivisions of the disclosed functionality. 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).

[0034] The subsystems can be designed and integrated to achieve a desired net attribute signal-to-noise ratio. The net attribute signal is the portion of the near infrared spectrum that is specific to the attribute of interest because it is orthogonal to other sources of spectral dispersion. Figure 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 non-invasive attribute determination by quantitative near infrared spectroscopy.

[0035] The subsystems provide reproducible and preferably spatially uniform radiance of tissue, low tissue sampling error, depth targeting of appropriate layers of tissue, efficient collection of diffuse reflectance spectra from tissue, high optical throughput, high photometric accuracy, wide 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 in further detail below.

[0036] (Lighting / Modulation Subsystem) The illumination / modulation subsystem 100 generates the light used to interrogate a sample (e.g., human skin tissue). In classical spectroscopy using dispersive or interferometric spectrometers, the spectrum of a polychromatic light source (or light emanating from a sample of interest) is measured by spatially dispersing different wavelengths of light (e.g., using a prism or 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" the different wavelengths, either spatially or temporally, so that each wavelength can be measured substantially independently of the other wavelengths. Although dispersive and interferometric spectrometers are known in the art and can perform their functions well in some environments and applications, they may be limited in other applications and environments by their cost, size, fragility, signal-to-noise ratio (SNR), and complexity.

[0037] An advantage of the solid-state light sources incorporated in the disclosed system is that the intensity of the light sources can be modulated independently. Thus, multiple solid-state light sources can be used, each emitting different wavelengths of light modulated at a different frequency or collectively modulated according to a predefined scheme such as that defined by Hadamard or a similar approach. The independently modulated solid-state 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 an effective coalescence of the solid-state light source and the spectrometer into a single illumination / modulation subsystem, which can provide significant benefits in size, cost, energy consumption, and overall system stability, since the spectrometer as an independent subsystem is eliminated from the measurement system. Furthermore, since all wavelengths can be independently modulated and combined into a single beam, a single element photodetector (rather than an array of photodetectors) is suitable for detecting all analytical light. This can represent a significant reduction in system complexity and cost over systems and embodiments involving multiple photodetector elements.

[0038] Several parameters of a system 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 (e.g., spectral width, intensity) of the solid-state light sources, the stability and control of the solid-state light sources, and their optical combination. Because each solid-state light source is a discrete element, it may be advantageous to combine the output of multiple solid-state light sources into a single beam to be constantly introduced and collected from the sample.

[0039] Additionally, the modulation scheme for the solid-state light source must also be considered, as some types of light sources may be susceptible to sinusoidal modulation of intensity, while others may be subject to being switched on and off or may be square wave modulated. In the case of sinusoidal modulation, multiple solid-state light sources may be modulated at different frequencies based on the system electronics design. The light emitted by multiple light sources may 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 may be converted to an intensity versus wavelength spectrum via a Fourier or similar transform.

[0040] Alternatively, some solid-state light sources that are amenable to the Hadamard transform approach are switched between on and off states or square wave modulated. However, in some embodiments, the Hadamard method can be implemented in electronics because the solid-state light source can be cycled at high frequency, rather than a traditional Hadamard mask that blocks or passes different wavelengths at different times during the measurement. A Hadamard or similar transform can be used to determine the intensity versus wavelength spectrum. Those skilled in the art will recognize that there are alternatives to the Hadamard encoding approach that are equally suitable for the present invention.

[0041] In one embodiment, a 47-wavelength Hadamard encoding approach is utilized, depicted as a matrix of binary numbers. Each row corresponds to one state of the Hadamard scheme, and each column corresponds to a wavelength in the measurement system. For each state, a value of "1" indicates that the wavelength (e.g., a laser diode) is on for that state, while a value of "0" indicates that the wavelength is off for that state. Each measurement of each state corresponds to one scan. Light emitted by the illumination / modulation subsystem 100 is delivered to the sample by the sampling subsystem 200. A portion of that light is collected, detected, digitized, and recorded by a photodetector in the data collection subsystem 300. The next state in the Hadamard scheme (e.g., a different set of wavelengths is on for that state) is then measured and recorded. This continues until all Hadamard states have been measured (referred to herein as a "Hadamard cycle"). Once the Hadamard cycle is completed, the intensity versus wavelength spectrum is determined by calculating the dot product of the recorded intensity vs. state data and the inverse matrix of the Hadamard scheme. The example Hadamard encoding described above consists of 47 wavelengths, but one skilled in the art will recognize that Hadamard schemes with other numbers of wavelengths are equally suitable for the present invention.

[0042] Another advantage of solid-state light sources is that many types (e.g., laser diodes and VCSELs) emit a narrow range of wavelengths (which in part determine the effective resolution of the measurement). As a result, it is not necessary to shape or shrink the emission profile of the solid-state light source using optical filters or other approaches, since it is already narrow enough. This can be advantageous due to reduced system complexity and cost. Furthermore, the emission wavelength of some solid-state light sources, such as diode lasers and VCSELs, is tunable over a range of wavelengths, either via the supplied drive current, drive voltage, or by varying the temperature of the solid-state light source. The advantage of this approach is that if a given measurement requires a certain number of wavelengths, the system can achieve the requirement with fewer discrete solid-state light sources by tuning over their viable range. For example, if a non-invasive measurement required 20 wavelengths, 10 discrete diode lasers or VCSELs could be used, with each of the 10 being tuned to two different wavelengths during the course of the measurement. In this type of scheme, the Fourier or Hadamard approach remains appropriate by varying the modulation frequency for each tuning point of the solid-state light source, or by combining the modulation scheme with a scanning scheme. Furthermore, if the emission wavelength for a given laser shifts or changes over time, the tuning nature of a diode laser allows it to be returned to its target emission wavelength by changing its drive current / voltage, temperature, or a combination thereof.

[0043] 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 the skin, such as alcohol or substances of abuse, the near infrared (NIR) region from 1,000 nm to 2,500 nm can be important due to the sensitivity and specificity of the spectroscopic signal to the analyte of interest as well as other chemical species present in human skin (e.g., water). Furthermore, the absorbance of the analyte is low enough that near infrared light can penetrate several millimeters into the skin where the analyte of interest is present. The wavelength range from 2,000 nm to 2,500 nm can be particularly useful because it contains multiple bands rather than the weaker and less specific harmonics encountered in the 1,000 to 2,000 nm portion of the NIR.

[0044] In addition to commercially available LEDs, VCSELs, and diode lasers in the visible region of the spectrum, there are solid-state light sources available with emission wavelengths throughout the NIR region (1,000-2,500 nm). These solid-state light sources are suitable for the disclosed analyte and biometric property measurement system. Some examples of available NIR solid-state light sources are VCSELs produced by Vertilas μmbH, VCSELs available from Laser Components μmbH, quantum cascade lasers, laser diodes, or lasers and diodes available from Roithner Laser, Sacher Lasertechnik, NanoPlus, Mitsubishi, Epitex, Dora Texas Corporation, Microsensor Tech, SciTech Instruments, Laser 2000, Redwave Labs, and Deep Red Tech. These examples are included for illustrative purposes and are not intended to limit the types of solid-state light sources suitable for use with the present invention.

[0045] A microcontroller can be used to control each solid-state light source in an embodiment of the illumination / modulation subsystem 100. The microcontroller can be programmed to include states defined by a Hadamard or other encoding scheme (e.g., individual solid-state light sources are turned off and on according to a set of states defined by the scheme). The microcontroller can then cycle through each of the states with a predetermined measurement time in each state. There is no restriction that the measurement time for each state must be equal. In addition to "off" and "on" control of each solid-state light source, the microcontroller can also provide global (across all solid-state light sources) and individual set points for the temperature and drive current / voltage of the solid-state light sources. Such an embodiment allows for control of wavelength tuning and / or improved stability of the illumination / modulation subsystem 100. Those skilled in the art will recognize that alternative microcontrollers are available that perform substantially the same functions as the described microcontroller embodiment.

[0046] (Measurement resolution and resolution enhancement) In dispersive spectrometers, the effective resolution of the spectroscopic measurement is often determined by the width of the aperture in the system. The resolution limiting aperture is often the width of the entrance slit. At the focal plane where the light in the spectrometer is detected, multiple images of the slit are formed at different wavelengths located at different spatial locations on the focal plane. Thus, the ability to detect one wavelength independent of its neighbors depends on the width of the slit. A narrower width allows better resolution between wavelengths at the expense of the amount of light that can pass through the spectrometer. As a result, the resolution and signal-to-noise ratio generally cancel each other out. Interferometric spectrometers have a similar trade-off between resolution and signal-to-noise ratio. In the case of a Michelson interferometer, the spectral resolution is determined in part by the distance the moving mirror is translated, with longer distances resulting in better resolution. The result is that the greater the distance, the more time is required to complete a scan.

[0047] For a measurement system, the spectral resolution is determined by the spectral width of each of the discrete solid-state light sources (whether different solid-state light sources, solid-state light sources tuned to multiple wavelengths, or a combination thereof). For measurements of analyte properties requiring high resolution, diode lasers or other suitable solid-state lasers can be used. The width of the laser's emission can be very narrow, resulting in high resolution. For measurement applications where modulation to lower resolution is required, LEDs may be preferred as they typically have a broader emission profile (output intensity distributed over a wide range of wavelengths) than solid-state laser alternatives.

[0048] The effective resolution of a solid-state light source can be increased through the use or combination of different types of optical filters. The spectral width of a solid-state light source can be reduced or attenuated using one or more optical filters to achieve higher resolution (e.g., a tighter range of emission wavelengths). Examples of optical filters contemplated in embodiments of the present invention include, but are not limited to, linear variable filters (LVFs), dielectric stacks, distributed Bragg gratings, photonic crystal lattice filters, polymer films, absorptive filters, reflective filters, etalons, dispersive elements such as prisms and gratings, and quantum dot filters.

[0049] 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 differences that exist between two or more overlapping wide solid-state light sources. For example, two solid-state light sources with partially overlapping emission profiles can be incorporated into a measurement system. Measurements can be collected from a sample, and a spectrum can be generated (via Hadamard, Fourier transform, or other suitable transform). Once the emission profile of the solid-state light source is known, the profile can be deconvoluted from the spectrum to enhance the resolution of the spectrum.

[0050] (Solid-state light source wavelength and intensity stabilization and control) 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 solid-state light source. In the case of semiconductor lasers, changing the thermal state or electrical properties alters the optical properties or physical dimensions of the semiconductor lattice structure. The result is a change in cavity spacing within the device, altering the emitted wavelength peak wavelength. Because solid-state light sources exhibit these effects, the stability of the peak emission wavelength and its associated intensity can be an important parameter when they are used in spectroscopic measurement systems. As a result, measurement control of both the thermal state or electrical properties of each solid-state light source can be advantageous in terms of overall system robustness and performance. Furthermore, changes in optical properties caused by thermal states or electrical properties can be exploited to allow a single solid-state light source to be tuned to multiple peak wavelength locations. This can result in an analyte property measurement system that can measure many more wavelength locations than a number of discrete solid-state light sources, which can reduce system cost and complexity.

[0051] Temperature stabilization can be achieved using multiple approaches. In some embodiments, one or more solid-state light sources can be stabilized by raising the temperature above (or cooling below) ambient conditions without additional control of the temperature. In other embodiments, one or more solid-state light sources can be actively controlled (either cooled or heated) to a set temperature using a control loop. For example, a temperature loop circuit suitable for embodiments of the present invention may include a TE-Cooled VCSEL package that includes a thermoelectric cooler and a precision thermistor. The precision thermistor may be connected to a Wheatstone bridge, which may be connected to a current drive circuit configured to drive the thermoelectric cooler.

[0052] The electrical properties of the solid-state light source also affect the emission profile (e.g., location of emission wavelength) of the solid-state light source. It may be advantageous to stabilize the current and / or voltage supplied to one or more solid-state light sources. For example, the peak emission of VCSELs and many diode lasers depends on the drive current. For embodiments in which stability of the peak wavelength is important, the stability of the drive current becomes an important figure of merit. In such cases, electronic circuits can be designed to provide a stable drive current to the VCSEL or diode laser. The complexity and cost of the circuit may depend on the required stability of the drive current. FIG. 3 illustrates a current drive circuit suitable for use with embodiments of the present invention. Those skilled in the art will recognize that alternative embodiments of current control circuits are known in the art and may also be suitable for the present invention. Additionally, some solid-state light sources require control of the drive voltage rather than the drive current, and those skilled in the art will recognize that electronic circuits designed to control voltage rather than current are readily available.

[0053] In some embodiments, a single solid-state light source, such as a VCSEL or diode laser, is tuned to multiple wavelengths over the course of a measurement. To achieve tuning of the solid-state light source, the circuit shown in FIG. 3 can be modified to include temperature set point and current control, respectively. In some embodiments, tuning of either temperature or drive current / voltage may be sufficient to achieve the desired tuning of the peak emission wavelength. In other embodiments, control of both temperature and drive current / voltage may be required to achieve the desired tuning range.

[0054] Additionally, optical means for measuring and stabilizing the peak emission wavelength can also be incorporated into the systems described in connection with the embodiments of 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 or diode laser peak wavelength. This example embodiment of the etalon uses a thermally stabilized flat fused quartz plate with a partially mirrored surface. For systems where each VCSEL or diode laser is required to provide multiple wavelengths, the free spectral range of the etalon can be selected so that its transmission peak matches the desired wavelength interval for tuning. Those skilled in the art will recognize that there are many optical configurations and electronic control circuits that are viable for this application. An alternative wavelength encoding scheme uses a dispersive grating and a secondary array detector to encode the VCSEL or diode laser wavelength to a spatial location on the array. For either the dispersive or etalon-based scheme, a secondary photodetector can be used that has less stringent performance requirements than the primary photodetector. Active control can reduce the stability requirements of the VCSEL temperature and current control circuitry by allowing real-time correction for any drift.

[0055] Embodiments and Approaches for Multi-Wavelength Illumination / Modulation Subsystems FIG. 5 illustrates an example embodiment of an illumination / modulation subsystem 100 in which ten individual solid-state light sources 101 are arranged in a planar array. In some embodiments of FIG. 5, the solid-state light sources 101 are individually housed in their own packages, such as TO-9, TO-56, or other standard packages. These packages may or may not be sealed with a transmissive window. In other embodiments, the solid-state light sources 101 may be disposed on a common carrier and the resulting assembly may be disposed into an enclosure. The enclosure may or may not be sealed. The temperature of each solid-state light source 101 may be independently controlled, with each having its own means for controlling temperature or collectively using a single means for controlling temperature.

[0056] Light emitted by the solid-state light sources 101 is collected and homogenized by homogenizer 102 (FIG. 5) and delivered to the input of the sampling subsystem 200. In some embodiments of the present invention, packing density (how close the individual solid-state light sources 101 can be placed relative to one another) is disadvantageous, limiting the number of solid-state light sources 101 that can be used. In such embodiments, a means for concentrating the light emitted by the solid-state light sources 101 into a smaller area may be advantageous. Means for efficient concentration and coupling of light into the sampling subsystem 200 are discussed in subsequent paragraphs.

[0057] In some embodiments, an alternative to a planar array of discrete solid-state light sources is employed. An example of a discrete solid-state light source 101, a laser diode, is shown in Figure 6 and consists of a semiconductor chip 103 and a laser emitting aperture 104.

[0058] In another embodiment, a cumulative number of individual solid-state light sources 101 are divided into one or more groups. Each solid-state light source 101 in the one or more groups is mounted on a common carrier 105 with a predefined spacing between the other solid-state light sources 101 (one carrier per group). This approach is called a light source "carrier" 104 and is depicted in FIG. 7. The carrier 105 may be formed, for example, from ceramic. In this embodiment, different wavelengths can come from different light sources, e.g., different wafers that are diced into laser chips. Multiple laser chips may form the solid-state light source 101. This allows multiple wavelengths to be accommodated by combining lasers from several sources (wafers, different vendors, etc.). The advantage of this approach is a smaller number of solid-state light source assemblies and a known relationship of the locations of the solid-state light sources relative to each other. This in turn allows the possibility of a reduced number of temperature control packages for the control of the individual solid-state light sources. Furthermore, a more efficient light coupling approach is enabled because the solid-state light sources within the package are in fixed and known locations relative to each other.

[0059] In other embodiments, multiple solid-state light sources are located within the same physical semiconductor to further reduce the number of parts in the illumination / modulation subsystem 100. In such embodiments, the solid-state light sources 101 within the semiconductor can be the same wavelength, different wavelengths, or a combination thereof. When the solid-state light sources 101 are laser diodes or other solid-state lasers, these embodiments are referred to as "laser bars" 106. As with the carrier embodiments, an advantage of the laser bar 106 is the very well characterized and identified location of each solid-state light source 101. Overall, the laser bar 106 provides a significant reduction in the number of discrete semiconductors, the total number of system components, and therefore the subsystem complexity and cost.

[0060] To increase the light intensity at the same wavelength, multiple solid-state light sources 101 of that wavelength can be used. In some embodiments, the solid-state light sources 101 of the same wavelength are adjacent and very close to each other to allow efficient light coupling. FIG. 8 shows a laser bar 106 consisting of 12 groups of two laser diodes (total of 24 laser emitters). The two lasers forming a pair 107 have a common wavelength, and each pair 107 has a different wavelength from the other pairs (12 distinct wavelengths across the bar 106 in this embodiment). Each pair 107 is spaced 480 microns from the adjacent pair 107, and the spacing between the two emitters 101 of a pair 107 is 5 microns. In an embodiment employing DFB diode lasers, the different wavelengths are achieved using a single semiconductor chip by applying gratings with different pitches to each pair 107. The emission of DFB lasers is generally single mode, which is advantageous in some embodiments. Those skilled in the art will recognize the numerous permutations of all-solid-state light sources 101 and their emission wavelengths encompassed by the carrier 105 and bar embodiments 106. The embodiments disclosed herein are not intended to limit the scope of the invention.

[0061] In some embodiments, a dedicated thermoelectric cooler for each emitter may be cost-prohibitive and size-prohibitive, and a single global cooler or temperature control may not provide sufficient local temperature control. In such cases, a local heating facility near the solid-state light source can be used to achieve local temperature control within the semiconductor. An embodiment of the heating facility is a local resistor near the solid-state light source that allows the applied current to be converted into local heat. This approach allows a single temperature control facility to apply the majority of the heating / cooling load, while the local facility allows fine tuning of each solid-state light source. This allows both a higher degree of stability as well as the ability to tune the emission wavelength of each laser by varying the local temperature.

[0062] Strategies for efficient coupling of solid-state light sources to sampling subsystems Whether the solid-state light sources of the embodiments are in individual packages or grouped on a smaller number of carriers or bars, the density of the light emitting apertures of the solid-state light sources is not ideal because there is always a finite distance between adjacent solid-state light sources. This spacing can be driven, for example, by the size of the individual solid-state light source packages, as well as the need for finite spacing to allow heat to dissipate. In some embodiments of the invention, the density of the light emitting apertures is not a concern, and a light homogenizer whose cross section is large enough to encompass the light emitting apertures of all the solid-state light sources in the illumination / modulation subsystem 100 can be used to collect, combine, and homogenize the output of the individual solid-state light sources. However, in this case, the photon flux at the output of the light homogenizer is lower than ideal because the light from the solid-state light sources is distributed substantially uniformly over the entire area of ​​the cross section. This corresponds to a reduction in the etendue of the system, which can be disadvantageous in some embodiments.

[0063] In embodiments where the reduction in etendue should be minimized, there are several strategies to more efficiently combine the output of the emitting apertures of the individual solid-state light sources. Some of the embodiments of the invention incorporate optical fibers 108 as a means to collect light from a solid-state light source 101 or pair of solid-state light sources 107 and combine it with light collected from other solid-state light sources 101 or pair of solid-state light sources 107 in the system (see FIG. 9). Multiple individual optical fibers 108 may be bundled into a cable 109. In one embodiment, as illustrated in FIG. 13, a fiber 108 collects light from each of 12 solid-state light sources 101 or pair of solid-state light sources 107. Twelve fibers 108 may be bundled into a cable 109. The emitting apertures of many solid-state light sources may be on the order of a few microns in diameter. Some of the embodiments of the invention may use large-core multimode optical fibers (as opposed to small-core single-mode fibers often used in telecommunications). The large fiber diameter relative to the small diameter of the emitting apertures allows the optical fiber to collect light from the emitting apertures with alignment tolerances of tens of microns at all diameters. Depending on the spacing of the emitting apertures and the size of the optical fiber 108, a given optical fiber can collect light from more than one aperture (see FIG. 9).

[0064] The advantage of such an approach is that it allows the output of any number of solid-state light sources to be combined by using an equal or fewer number of optical fibers. Opposite ends of the optical fibers can then be assembled into a bundle. In some embodiments, the bundle is a circular hexagonal pack. For a given number of fibers of a given diameter, this configuration represents the smallest cross-sectional area, thus preserving the maximum photon flux and etendue. Furthermore, optical fibers allow linear or other geometric arrangements of solid-state light sources (e.g., laser bars, etc.) to be fabricated while retaining the ability to incorporate their output into a small area aperture that allows efficient coupling of collected light into the sampling subsystem 200. The laser bar assembly may comprise a laser bar 106, a ceramic carrier 105 with electrical contacts, an optical fiber coupler (not shown), a copper microbench (not shown), and a thermoelectric cooler (not shown). The assembly can be housed in a hermetic package, such as an industry-standard butterfly package. In some embodiments, an optical homogenizer can be placed at the output of the optical fiber bundle to spatially and / or angularly homogenize the output of the individual optical fibers. In such embodiments, the cross-sectional area can be matched to the area of ​​the optical fiber bundle to minimize any reduction in photon flux and etendue. In some embodiments, the arrangement of optical fibers in the output bundle can be matched to the cross-section of the light homogenizer (e.g., square, hexagonal, etc.).

[0065] The fiber optic coupling approach also allows multiple assemblies with solid-state light source apertures to be assembled into a single output aperture. For example, FIG. 10 shows four laser bars 106, each with 12 laser emitter pairs 107 (see FIG. 8). A multimode optical fiber 110 may be used to collect light from each emitter pair 107 (for a total of 48 fibers 108). The opposing ends of the 48 fibers 108 are then assembled into a circular hex-pack output ferrule 111.

[0066] (Method and Apparatus for Homogenization of Illumination / Modulation Subsystem Output) In order to provide a reproducible and preferably uniform radiance at the input of the tissue sampling subsystem 200, a light homogenizer 112, such as an optical diffuser, light pipe, and other scrambler, can be incorporated into some embodiments of the illumination / modulation subsystem 100. FIG. 11 shows an example light homogenizer 112 comprising a ground diffuser with two opposing bends and a hexagonal cross-section light pipe. Uniform radiance can ensure good photometric accuracy and even illumination of the tissue. Uniform radiance can also reduce errors associated with manufacturing differences between solid-state light sources. To achieve accurate and precise measurements, uniform radiance can be utilized in various embodiments of the present invention. See, for example, U.S. Pat. No. 6,684,099, which is incorporated herein by reference.

[0067] A ground glass plate is an example of an optical diffuser. The polished surface of the plate effectively scrambles the radiation angle emanating from the solid-state light source and its transmission optics. A light pipe can be used to homogenize the intensity of the radiation so that it is spatially uniform at the output of the light pipe. In addition, a light pipe with a double bend will scramble the radiation angle. To create a 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 be directly coupled to the input of the tissue sampler or can be used in conjunction with additional transmission optics before the light is sent to the tissue sampler. See, for example, U.S. Patent Application Serial No. 09 / 832,586, "Illumination Device and Method for Spectroscopic Analysis," incorporated herein by reference.

[0068] (Sampling Subsystem) FIG. 1 shows the orientation of the tissue sampling subsystem 200 between the illumination / modulation (100) and data collection (300) subsystems. With reference to FIG. 1, the tissue sampling subsystem 200 introduces radiation generated by the illumination / modulation subsystem 100 into a sample (e.g., tissue of interest), collects a portion of the radiation not absorbed by the sample, and transmits the radiation to a photodetector in the data collection subsystem 300 for measurement. FIGS. 12 through 17 depict elements of an example tissue sampling subsystem 200. With reference to FIG. 12, the tissue sampling subsystem 200 has an optical input 202, a sampling surface 204 forming a tissue interface 206 for interrogating tissue, and an optical output 207. The subsystem further includes an ergonomic device 210, depicted in FIG. 13, that holds the sampling surface 204 and positions the tissue at the interface 206. The output 211 transmits a signal to a processing circuit, which may be, for example, a microprocessor. In the exemplary subsystem, a device for thermoregulating the tissue interface is included in some embodiments. In other embodiments, an index matching fluid can be used to improve the optical interface between the tissue and the sampling surface. The improved interface can reduce errors and increase efficiency, thereby improving the net attribute signal. See, for example, U.S. Patent Nos. 6,622,032, 6,152,876, 5,823,951, and 5,655,530, each of which is incorporated herein by reference.

[0069] 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 transmits the radiation to the tissue interface 206. As an example, the optical input can comprise a fiber optic bundle arranged in a geometric pattern that collects an appropriate amount of light from the illumination / modulation subsystem. FIG. 14 depicts one example arrangement. A top view depicts the geometric shape of the ends of the input and output fibers at the sampling surface, including six clusters 208 arranged in a circular pattern. Each cluster includes four central output fibers 212 that collect light diffusely reflected from the tissue. Surrounding each grouping of four central output fibers 212 is a cylinder 215 of material that ensures a gap of approximately 100 μm between the edge of the central output fibers 212 and the inner ring of input fibers 214. A gap of 100 μm may be important for measuring ethanol within the dermis. As shown in Figure 14, two concentric rings of input fibers 214 are arranged around a cylinder of material 215. As shown in one example embodiment, 32 input fibers surround 4 output fibers.

[0070] FIG. 15 demonstrates an alternative to the cluster geometry of the sampling subsystem. In this embodiment, the illumination and collection optical fibers are arranged in a linear geometry. Each row can be either for illumination or light collection, and can be any length suitable to achieve sufficient signal-to-noise. In addition, the number of rows can be two or more to modify the physical area covered by the sampling subsystem. The total number of potential illumination fibers depends on the physical size of the emission area of ​​the solid-state light source subsystem (e.g., the area of ​​the cross section of the fiber bundle or light homogenizer, depending on the embodiment), and the area of ​​each fiber. In some embodiments, multiple solid-state light source subsystems can be used to increase the number of illumination fibers. If the number of collection fibers results in an area larger than the photodetector of the data collection subsystem (300), 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 passing through the aperture. In some embodiments, the light homogenizer can be omitted and the aperture can be used alone. In other embodiments, the active area of ​​the detector acts as the aperture (e.g., there is no distinct aperture), in which case light that is not incident on the active area is effectively vignetted.

[0071] In some embodiments of the sampling subsystem (200) of the present invention, the portion of the optical probe that interacts with the sample can consist 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 appropriately designed for the sample and measurement location of interest (e.g., hand, finger). Figure 16 shows an example embodiment of a sampling subsystem based on a linear stack of ribbons. Additional details regarding preferred embodiments for use in the present invention can be found in co-pending U.S. patent applications Ser. Nos. 12 / 185,217 and 12 / 185,224, each of which is incorporated herein by reference.

[0072] In many embodiments of tissue analyte measurement devices, the photodetector is the limiting aperture of the system. In such systems, the system throughput (and correspondingly the signal-to-noise ratio, SNR) can be optimized by incorporating an optical probe design that illuminates a larger area of ​​the sample (tissue) while collecting light from a smaller aperture that matches the solid acceptance angle of the photodetector. With reference to the optical probe design of FIG. 16, each collection fiber (black circle) is surrounded by eight illumination fibers (white circles). For each collection fiber, this geometric difference in area allows each of the eight illumination fibers to contribute to the collected light. The net effect of this approach is to allow more light to be collected from the blackbody light source and delivered to the sample without being subject to vignetting by the limiting aperture. This can be advantageous for light sources that inherently have a wide emission area (such as many blackbody emitters).

[0073] However, the photon flux of a semiconductor light source such as a diode laser can be much higher than that of a blackbody light source. As a result, a limited number of semiconductor light sources can deliver comparable or superior photon flux with a smaller solid angle relative to their blackbody counterpart. This can result in a solid angle of photon emission (combined solid angle of all semiconductor light sources) that is smaller than the solid acceptance angle of the detector. In other words, the light source, rather than the photodetector, is the effective limiting aperture of the system. In such cases, optical probe designs such as those shown in FIG. 16 do not optimize the throughput and SNR of the system. Although such optical probes are suitable in some embodiments of the present invention, alternative embodiments may be preferred. In other embodiments, the number of illumination optical fibers may be equal to or less than the number of collection optical fibers. These optical probe designs have a sampling surface that allows for a small illumination area that matches the smaller area of ​​the solid-state light source's emission, along with a larger collection area that matches the larger area of ​​the photodetector. As a result, the overall efficiency of the system is improved.

[0074] The sampling subsystem may also use one or more channels, where a channel refers to a particular orientation of the illumination and collection fibers. The orientation consists 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 fibers or fibers. Multiple channels may be used together, either simultaneously or sequentially, to improve the accuracy of the non-invasive measurement. In one embodiment, a two-channel sampling subsystem is utilized. In this example, two channels are measuring the same tissue structure. Thus, each channel provides a measurement of the same tissue from a different perspective. The second perspective helps provide additional spectroscopic information that helps decouple the signal due to scattering and absorption. Referring to FIG. 17, a group of fibers (one light source, one receptor #1, and one receptor #2 in this example) may be replicated 1 to N times to increase the sampler area and improve optical efficiency. Each of the fibers may have a different numerical aperture and angle (0). The distance between fibers X and Y determines the source-receptor separation. Additionally, additional source channels can be added, creating a four-channel sampling subsystem. Those skilled in the art will recognize the numerous possible variations in the number and relationships between the channels.

[0075] In experiments where a multi-channel sampler was used for non-invasive glucose measurements, the results showed that a combination of two channels provided superior measurement accuracy when compared to either channel individually. Although this example uses two channels, additional channels can provide additional information that can further improve the measurement.

[0076] Another aspect of the multi-channel sampling subsystem is the ability to improve detection and mitigation of local interferents, such as sweat or lotion, present on the sample. Figure 17 is a schematic diagram of a multi-channel sampling subsystem in the presence of local interferents. Figure 17 shows the sampling subsystem, the layer of local interferents, and the tissue at the tissue interface. In this example, the contribution of the local interferents to the measurement of each channel is the same. This allows the possibility of decoupling a common local interferent signal present in both channels from the tissue signal, which would be different for the two channels.

[0077] 12, the clustered input and output fibers are mounted into cluster ferrules that are mounted into a sampling head 216. The sampling head 216 includes a sampling surface 204 that is polished flat to allow for a good tissue interface. Similarly, the input fibers are clustered into a ferrule 218 that is connected at the input end 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 collection subsystem 300.

[0078] Alternatively, the light input may use a combination of light pipes, refractive and / or reflective optics to deliver the input light to the tissue interface. It is important that the input optics of the tissue sampling subsystem collect enough light from the illumination / modulation subsystem 100 to achieve an acceptable net attribute signal.

[0079] The tissue interface can illuminate the tissue in a manner that targets tissue compartments for the desired attribute and discriminate light that does not travel a significant distance through these compartments. As an example, a 100 μm gap between the illumination and collection optical fibers can discriminate light that contains little attribute information. In addition, the tissue interface can average over an area of ​​a tissue to reduce errors due to the non-uniform nature of the tissue. The tissue sampling interface can reject specular, short path length light rays and collect the portion of light that travels a desired path length through the tissue with high efficiency to maximize the net attribute signal of the system. The tissue sampling interface can employ optical fibers to direct light from the input to the tissue in a predetermined geometry, as discussed above. The optical fibers can be arranged in a pattern that targets a layer of a tissue that contains good attribute information.

[0080] The spacing, angle, numerical aperture, and location of the input and output fibers can be arranged in a manner that achieves effective depth targeting. In addition to using 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 thermostatically regulated to control the temperature of the tissue in a predetermined manner. The temperature of the tissue sampling interface can be set such that prediction errors due to temperature fluctuations are reduced. Additionally, reference errors are reduced when building a calibration model. These methods are disclosed in U.S. Patent Application No. 09 / 343,800, entitled "Method and Apparatus for Non-Invasive Blood Analyte Measurement with Fluid Compartment Equilibration," which is incorporated herein by reference.

[0081] The tissue sampling subsystem 200 can employ an ergonomic device or guide 213 that positions the tissue over the sampling interface 204 in a reproducible manner. An example ergonomic device 213 that reproducibly guides the finger to the sampling surface is depicted in FIG. 13. The ergonomic device 213 includes a base 217 that includes an opening 219 therethrough. The opening 219 is sized to receive the sample head 216 therein so as to position the sampling surface 204 approximately flush with the top surface of the base. Careful attention must be paid to the ergonomics of the tissue sampling interface or significant sampling errors may occur. Alternative locations, such as the top or palmar side of the fingertip or forearm, can also be accommodated using variations of the system described herein.

[0082] The output of the tissue sampling subsystem 200 transmits the portion of light that has traveled an acceptable path through the tissue to a photodetector in the data collection subsystem 300 that is not absorbed by the tissue. 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 photodetector. In some embodiments, the collected light is homogenized to reduce spatial and angular effects that may be sample dependent (see U.S. Pat. No. 6,684,099, Apparatus and Methods for Reducing Spectral Complexity in Optical Sampling, incorporated herein by reference).

[0083] (Data Acquisition Subsystem) The data acquisition subsystem 300 converts the optical signal from the sampling subsystem into a digital representation. Figure 18 is a schematic diagram of the data acquisition subsystem 300. An advantage of at least one embodiment of the present invention is that, similar to an interferometer, 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.

[0084] The photodetector converts the incident light into an electrical signal as a function of time. Examples of detectors sensitive in the 1.0-2.5 μm spectral range include InGaAs, InAs, InSb, Ge, PbS, and PbSe. Example embodiments of the present invention may utilize a 1 mm thermoelectrically cooled extended range InGaAs detector sensitive to light in the 1.0-2.5 μm range. The 2.5 μm extended range InGaAs detector has low Johnson noise, resulting in shot noise limited performance for photon flux emanating from the tissue sampling subsystem. The extended InGaAs detector has a peak sensitivity in the 2.0-2.5 μm spectral region, where the three very important alcohol absorption features are located. Compared to a liquid nitrogen cooled InSb detector, the thermoelectrically cooled extended range InGaAs may be more practical for commercial use. This detector also exhibits linearity of 120 dBC or better in the 1.0-2.5 μm spectral range. If the alcohol measurement system utilizes an alternative wavelength range, an alternative detector may be preferred. For example, if the wavelength range of interest was within the 300-1100 nm range, a silicon detector would be suitable. Any photodetector can be used as long as the desired photodetector meets the basic sensitivity, noise, and speed requirements.

[0085] 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 a digital representation thereof using an analog-to-digital converter, digital filtering, and resampling of the digital signal from equal time intervals to equal position intervals. 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 an SNR and distortion of at least 100dbc. 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 kHz. In systems with only one channel of signal to digitize (instead of two or more as is common in delta-sigma ADCs), the signal can be passed into both inputs of the ADC and averaged following digitization. This operation can help reduce any uncorrelated noise introduced by the ADC. If system performance requirements permit, an alternative analog-to-digital converter can be used in which sample acquisition is synchronized with the solid-state light source modulation, rather than captured at equal time intervals. The digitized signal may be passed to a computer subsystem 400 for further processing, as discussed below.

[0086] The constant time sampling data acquisition subsystem 300 has several distinct advantages over other methods of digitizing signals. These advantages include wider 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 in the analog electronics prior to the ADC. This includes nonlinear phase errors in the amplification and filtering circuits, as well as the non-ideal frequency response of the photodetector. The uniformly sampled digital signal allows the application of one or more digital filters whose cumulative frequency response is the inverse of the transfer function of the analog electronics (see, for example, U.S. Pat. No. 7,446,878, incorporated herein by reference).

[0087] (Computer Subsystem 400) The computer subsystem 400 performs several functions, such as converting the digitized data obtained from the data collection subsystem 300 into intensity versus wavelength spectra, performing spectral outlier checks on the spectra, spectral pre-processing in preparation for determining attributes of interest, determining attributes of interest, system status checks, display and processing requirements associated with a user interface, and data transfer and storage. In some embodiments, the computer subsystem is contained in a dedicated personal or laptop computer that is connected to other subsystems of the invention. In other embodiments, the computer subsystem is a dedicated embedded computer.

[0088] After converting the digitized data from the detector into an intensity versus wavelength spectrum, the computer system can check the spectrum for outliers or bad scans. An outlier sample or bad scan is one that violates the assumed relationship between the measured signal and the property of interest. Examples of outlier conditions include conditions where a calibrated instrument is operated outside of a specified operating range, such as ambient temperature, ambient humidity, vibration tolerance, component tolerances, power levels, etc. Additionally, outliers can occur when the composition or concentration of a sample differs from the composition or concentration range of the sample used to build a calibration model. Calibration models are discussed later in this disclosure. Outliers or bad scans can be removed and the remaining good spectra can be averaged together to produce an average single beam spectrum for the measurement. The intensity spectrum can be converted to absorbance by taking the base-10 logarithm (-log10) of the spectrum. The absorbance spectrum can be scaled to renormalize noise.

[0089] The scaled absorbance spectrum can be used in conjunction with the calibration model obtained from the calibration subsystem 500 to determine the attribute of interest. After determining the attribute of interest, the computer subsystem 400 can report the result 830, for example, to the subject, to an operator or administrator, to a record system, or remotely to a monitor. The computer subsystem 400 can also report a level of confidence in the goodness of the result. If the confidence level is low, the computer subsystem 400 can withhold the result and ask the subject to retest. If necessary, additional information can be conveyed to instruct the user to take corrective action. See, for example, U.S. Application No. 20040204868, which is 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, telephone lines, or cell phone service.

[0090] The computer subsystem 400 includes a central processing unit (CPU), memory, storage, a display, and preferably a communication link. An example of a CPU is an Intel Pentium microprocessor. The memory can be static random access memory (RAM) and / or dynamic random access memory. The storage can be accomplished using non-volatile RAM or a disk drive. A liquid crystal, LED, or other display can be suitable. The communication link can be a high speed serial link, an Ethernet link, or a wireless communication link, as examples. The computer subsystem can, for example, generate attribute measurements from received and processed interferograms, perform calibration maintenance, perform calibration moves, perform equipment diagnostics, store a history of measured alcohol concentrations and other related information, and in some embodiments, communicate with a remote host to send and receive data and new software updates.

[0091] The computer system 400 can also contain a communication link that allows the transfer of the subject's alcohol measurement record and corresponding spectrum 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 considered an information appliance. Examples of information appliances include personal digital assistants, web-enabled mobile phones, and handheld computers.

[0092] (Calibration Subsystem 500) A calibration model is used in conjunction with the spectral information to obtain the alcohol measurement. In some embodiments, the calibration model is formed by collecting blood reference measurements and simultaneous spectroscopic data for multiple subjects at a wide variety of environmental conditions. In these embodiments, spectroscopic data can be collected from each subject across a range of blood alcohol concentrations. In other embodiments, the hybrid calibration model can be one that measures the alcohol concentration of the subject spectrum. In this case, the term hybrid model denotes that a combination of in vitro and in vivo spectral data was used to create a partial least squares (PLS) calibration model. The in vitro portion of the data was a 0.1 mm path length transmission spectrum of 500 mg / dL alcohol in water measured using a non-invasive measurement system configured for transmission measurements. The transmission spectrum was proportional to the 0.1 mm path length transmission spectrum of water, converted to absorbance, and normalized to unit path length and concentration.

[0093] Light propagation through tissue is a complex function of diffuse reflectance optical tissue sampler design, physiological variables, and wavenumber. As a result, the path length of light through tissue has a wavenumber dependence that is not encountered in dispersion-free transmission measurements. To address the wavenumber dependence, the optical tissue sampler's interaction with the scattering properties of human tissue was modeled via Monte Carlo simulations using a commercially available ray tracing software package (TracePro). Using the resulting model of light-tissue interaction, estimates of the effective path length of light through the dermis and subcutaneous tissue layers as a function of wavenumber were generated. The effective path length (1 eff ) is defined as follows:

[0094]

number

[0046] Due to its large absorption in vivo, water is the only analyte that significantly affects the effective path length. Therefore, for purposes of the effective path length calculation, the absorption coefficient used was that of water at physiological concentrations. The alcohol absorbance spectrum (as measured in transmittance) was then scaled by the calculated path function to form a corrected alcohol spectrum that represents the wavenumber-dependent path length measured by the diffuse reflectance optical sampler. This corrected spectrum formed the basis spectrum for the mathematical addition of alcohol to the calibration spectrum.

[0095] The in vivo data included non-invasive tissue spectra collected from individuals not consuming alcohol. A hybrid model was formed by adding alcohol pure component spectra weighted by various alcohol "concentrations" (ranging from 0 to 160 mg / dL) to the non-invasive tissue spectral data. A PLS calibration model was constructed by regressing the synthetic alcohol concentrations on the hybrid spectral data. Figure 19 is a schematic of the hybrid calibration formation process. The hybrid calibration in this study used approximately 1500 non-invasive tissue spectra collected from 133 subjects over a 3-month period.

[0096] The use of a hybrid calibration model, rather than a calibration model constructed from spectra collected from subjects that consumed alcohol, can provide significant advantages. The hybrid modeling process allows for the generation of calibration spectra that contain higher concentrations of alcohol (up to 160 mg / dL in this study) than would be considered safe for consumption in human subject studies (120 mg / dL being the upper safe limit). This can result in a more powerful calibration with a wider range of analyte concentrations that can more accurately predict higher alcohol concentrations. This can be important because alcohol concentrations observed in the field can be more than twice the maximum safe dose in a clinical research environment. The hybrid calibration process also allows for the prevention of correlation between alcohol and spectral interferents in tissues. For example, the random addition of alcohol signal to the calibration spectrum would prevent alcohol concentration from correlating with water concentration. Thus, the hybrid approach prevents the possibility that measurements may erroneously track changes in tissue water content instead of alcohol concentration.

[0097] Once formed, it is desirable for the calibration to remain stable and produce accurate attribute predictions over time. This process is called calibration maintenance and can consist of multiple methods that can be used individually or together. The first method is to create the calibration in a manner that makes it inherently robust. Several different types of instrumental and environmental variations can affect the predictive ability of a calibration model. It is possible, and desirable, to reduce the magnitude of the effect of this variation by incorporating instrumental and environmental variations into the calibration model.

[0098] However, it is difficult to span the entire possible range of instrument conditions during a calibration period. System permutations may cause the instrument to operate outside the space of the calibration model. Measurements made while the instrument is in an improperly modeled state may exhibit prediction errors. For in vivo optical measurements of medically significant attributes, these types of errors may result in erroneous measurements that reduce the usefulness of the system. Therefore, it is often advantageous to use additional calibration maintenance techniques during the instrument's life to continually verify and correct the instrument's condition.

[0099] Examples of problematic equipment and environmental variations include, but are not limited to, changes in the levels of environmental interferents such as water vapor or CO2 gas, changes in the alignment of the optical components of the equipment, variations in the output power of the equipment's illumination system, and changes in the spatial and angular distribution of the light output by the equipment's illumination system.

[0100] 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. Some of the disclosed methods use environmentally inert, non-tissue samples, such as integrating spheres, that may or may not contain attributes of interest to monitor the instrument over time. The samples can be incorporated into the optical path of the instrument or interface using a sampling subsystem, similar to tissue measurements. The samples can use transmittance or reflectance, contain stable spectral features, or do not contribute any respective spectral features. The material can be a solid, liquid, or gel material, so long as the spectrum is stable or predictable over time. Any unexplained change in the spectrum collected from the sample over time indicates that the instrument is undergoing perturbation or drift due to environmental influences. The spectral change can then be used to correct subsequent tissue measurements in humans to ensure accurate attribute measurements.

[0101] Another means to achieve successful calibration maintenance is to update the calibration using measurements collected on the device over time. Usually, knowledge of a reference value of the analyte property of interest is required to perform such an update. However, in some applications, the reference value is usually, but not necessarily, known to be a specific value. In this case, this knowledge can be used to update the calibration even if the specific value of the analyte property is not known for each measurement. For example, in alcohol screening in residential care facilities, the majority of measurements performed by individuals are performed on individuals who follow alcohol consumption limits and therefore have an alcohol concentration of zero. In this case, the alcohol concentration measurement or related spectrum obtained from the device disclosed according to various embodiments of the present invention can be used in conjunction with the estimated zero as a reference value. Thus, the calibration can be updated to include new information as it is collected in the field. This approach can also be used to perform calibration moves, since measurements with the estimated zero can be used at the time of system manufacture or installation to remove any system-specific bias in the analyte property of interest measurements. Calibration maintenance updates or calibration movement implementations 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 central or moving windows, principal component analysis, or combinations thereof.

[0102] Once a calibration is developed, it is often desirable to transfer the calibration to all existing and future units. This process is commonly referred to as a calibration transfer. Although not required, a 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 the success or failure of a product. Calibration transfer arises from the fact that optical and electronic components vary from unit to unit, which in the aggregate can result in significant differences in the spectra acquired from multiple instruments. For example, two solid-state light sources can have different color temperatures, thereby resulting in different light distributions for the two sources. The responsivity of the two detectors can also be significantly different, resulting in additional spectral differences.

[0103] Similar to calibration maintenance, several methods can be used to effectively achieve calibration transfer. The first method is to build a calibration using multiple instruments. The presence of multiple instruments allows the spectral variations associated with instrument differences to be determined and made orthogonal to the attribute signal during the calibration formation process. This approach reduces the net attribute signal, but can be an effective means of calibration transfer.

[0104] The additive calibration transfer method involves explicitly determining the difference in the spectral characteristics of the system relative to those used to build the calibration. In this case, the spectral differences can then be used to correct the spectral measurements prior to attribute prediction on the system, or can be used to directly correct the predicted attribute values. The instrument-specific spectral characteristics can be determined from the relative differences in the spectra of stable samples collected from the system of interest and those used to build the calibration. The samples described in the calibration maintenance section are also applicable to the calibration transfer. See, for example, U.S. Patent No. 6,441,388, "Method and Apparatus for Spectroscopic Calibration Transfer," incorporated herein by reference.

[0105] (Alcohol measurement method) Depending on the intended application, measurements of analyte properties can be considered in terms of two modalities. The first modality is "walk-up" or "generic" and refers to analyte properties where previous measurements of a sample (e.g., subject) are not used in determining the analyte property from the current intended measurement. When measuring in vivo alcohol, drunk driving practices fall into this modality since in most cases the individual being tested will not have been previously measured with a breathalyzer device. Thus, no prior knowledge of the individual is available for the current determination of the analyte property.

[0106] The second modality is referred to as "registration" or "adjustment" and refers to situations where previous measurements from a sample or subject are available in determining the analyte properties of a current measurement. An example of an environment where this modality can be applied is an automobile interlock, where a limited number of people are permitted to drive or operate a car or machine. Additional information regarding embodiments of registration or adjustment applications can be found in U.S. Patent Nos. 6,157,041 and 6,528,809, entitled "Method and Apparatus for Tailoring Spectroscopic Calibration Models," each of which is incorporated herein by reference. In registration applications, the combination of measurements of analyte properties with biometric measurements can be particularly advantageous, since the analyte properties can assess health levels (e.g., sobriety) while the same spectroscopic measurements can assess whether a predictive operator is authorized to use the device or car via a biometric.

[0107] Method for determining biometric verification or identification from a spectroscopic signal Biometric identification describes the process of using one or more physical or behavioral characteristics to identify an individual or other biological entity. There are two common biometric modes: identification and verification. Biometric identification seeks to answer the question "Do I know you?" A biometric measurement device collects a set of biometric data from a target individual. From this information alone, it evaluates whether the individual has been previously enrolled in the biometric system. Systems that perform biometric identification tasks, such as the FBI's Automated Fingerprint Identification System (AFIS), are generally very expensive (millions of dollars or more) and require many minutes to find a match between an unknown sample and a vast database containing hundreds of thousands or millions of entries. In biometric verification, the relevant question is "Are you who you claim to be?" This mode is used when an individual claims an identity using a code, magnetic card, or other means, and the device uses the biometric data to verify the individual's identity by comparing the target biometric data with enrollment data corresponding to the intended identity. The present apparatus and method for monitoring the presence or concentration of alcohol or abused substances in a controlled environment can use either biometric mode.

[0108] There is also at least one variation between these two modes that is suitable for use in various embodiments of the present invention. This variation occurs when a small number of individuals are contained in the enrollment database and the biometric application only requires a determination of whether the target individual is among the enrolled set. In this case, the exact identity of the individual is not required, and therefore the task is somewhat different from (and often easier than) the identification task described above. This variation may be useful in applications where the biometric system is used in a method where the tested individual must be part of an approved group and not intoxicated, but the specific identity of the individual is not required. The term "identity characteristic" includes all of the above modes, variations, and their combinations or modifications.

[0109] There are three main data elements associated with biometric measurements: calibration, enrollment, and target spectral data. Calibration data is used to establish the spectral features that are important for biometric determination. This set of data consists of a series of spectroscopic tissue measurements collected from one or more individuals of known identity. Preferably, these data are collected over a period of time and set of conditions such that, while multiple spectra are collected for each individual, they span the full range of physiological conditions that the individual is expected to experience. In addition, the instrument or instruments used for spectral collection should also generally span the full range of instrument and environmental effects that it or a sister instrument is likely to encounter during 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 inter-individual spectral differences while minimizing sensitivity to intra-individual, instrument (both intra- and inter-instrument), and environmental effects. These wavelengths or factors are then used later to perform the biometric determination task.

[0110] The second main set of spectral data used in biometric determination is the enrollment spectral data. The purpose of the enrollment spectrum for a given subject or individual is to generate a "representation" of the subject's unique spectral characteristics. Enrollment spectra are collected from individuals who need to be approved or otherwise recognized by the biometric system. Each enrollment spectrum can be collected over a period of a few seconds or minutes. Two or more enrollment measurements can be collected from an individual to ensure similarity between the measurements and to exclude one or more measurements if an artifact is 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, combined differently, or stored separately. In either case, the data is stored in an enrollment database. In some cases, each set of enrollment data is tied to an identifier (e.g., a password or key code) of the individual whose spectrum was measured. For identification tasks, the identifier can be used for record-keeping purposes of who accessed the biometric system and when. For verification tasks, the identifier is used to extract the correct set of enrollment data against which verification is performed.

[0111] The third and final major set of data used in biometric systems is the spectral data collected when an individual attempts to use the biometric system for identification or verification. These data are called target spectra. They are compared to measurements stored in the enrollment database (or a subset of the database in the case of identity verification) using 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, either all of the matching individuals can be reported or the best match can be reported as the identified individual. In the case of biometric verification, the target spectrum is accompanied by a claimed identity, collected using a magnetic card, a typed user name or identifier, a transponder, a signal from another biometric system, or other means. The claimed identity is then used to retrieve a corresponding set of spectral data from the enrollment database against which a biometric similarity determination is made and the identity is either verified or rejected. If there is insufficient similarity, the biometric determination may be cancelled and a new target measurement attempted.

[0112] In one method of verification, principal component analysis is applied to the calibration data to generate spectral factors. These factors are then applied to the resulting spectral differences between the target spectrum and the enrollment spectrum to generate Mahalanobis distance and spectral residual magnitude values ​​as similarity metrics. Identity is verified only if the distance and magnitude are less than the predetermined thresholds described for each. Similarly, in an example method of biometric identification, Mahalanobis distance and spectral residual magnitude are calculated for the target spectrum against each of the database spectra. The identity of the individual providing the test spectrum is established as the individual or individuals associated with the database measurements that yielded the minimum Mahalanobis distance and spectral residual magnitude that are less than the predetermined thresholds described for each.

[0113] In an example method, an identification or verification task is implemented when an individual attempts to perform an action for which a limited number of people are authorized (e.g., taking a spectroscopic measurement, entering a controlled facility, passing through an immigration checkpoint, etc.). The individual's spectral data is used to identify or verify the individual's identity. In this method, an individual first enrolls in the system by collecting one or more representative tissue spectra. If two or more spectra are collected during enrollment, these spectra may be checked for consistency and recorded only if they are sufficiently similar, limiting the possibility of sample artifacts corrupting the enrollment data. For a verification implementation, an identifier such as a PIN code, magnetic card number, user name, badge, voice pattern, other biometric, or some other identifier may also be collected and associated with one or more confirmed enrollment spectra.

[0114] During subsequent use, biometric identification can be performed by collecting a spectrum from the individual seeking approval. This spectrum can then be compared to spectra in an enrolled approval database, and identification can be made if the match to the approved database entry is better than a predefined threshold. The verification task is similar, but can require the individual to present an identifier in addition to the collected spectrum. The identifier can then be used to select a particular enrollment database spectrum, and approval can be granted if the current spectrum is sufficiently similar to the selected enrollment spectrum. In cases where the biometric task is associated with an operation for which only one individual is approved, the verification and identification tasks are identical, and both simplify to the confidence that only one approved individual is attempting the operation without the need for a separate identifier.

[0115] Biometric measurements, 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 or classification techniques. Some of these methods rely on establishing a base spectral shape (factors, weight vectors, eigenvectors, latent variables, etc.) in an intrapersonal calibration database and then using standard outlier methodologies (spectral F-ratio, Mahalanobis distance, Euclidean distance, etc.) to determine the consistency of the input measurements with the enrollment database. The base spectral shape can be generated by multiple means as disclosed herein.

[0116] First, the basis spectral shape can be generated based on a simple spectral decomposition (eigenanalysis, Fourier analysis, etc.) of the calibration data. A second method of generating the basis spectral shape involves the creation of a general model as described in U.S. Patent No. 6,157,041, entitled "Methods and Apparatus for Tailoring Spectroscopic Calibration Models," which is incorporated by reference. In this application, the basis spectral shape is generated through a calibration procedure performed on intrapersonal spectral features. The basis spectral shape can be generated by the creation of a calibration based on simulated configuration variations. The simulated configuration variations can model variations introduced by real physiological or environmental or instrumental variations, or can simply be artificial spectroscopic variations. It is recognized that other means of determining the basis shape will be applicable to the identification and verification methods of the disclosed embodiments of the present invention. These methods can be used either in conjunction with or in place of the techniques described above.

[0117] (Calibration Check Sample) In addition to disposable parts that ensure the safety of the subject, disposable calibration check samples can be used to verify that the instrument is in proper operating condition. In many commercial applications of alcohol measurement, the condition of the instrument must be verified to ensure that subsequent measurements will provide accurate alcohol concentration or attribute estimates. The condition of the instrument is often checked immediately prior to subject measurement. In some embodiments, the calibration check sample can include alcohol. In other embodiments, the check sample can be an environmentally stable, spectrally inert sample, such as an integrating sphere. The check sample can be a gas or liquid that is injected or flowed through the 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 can be incorporated into another area of ​​the optical path of the system. These examples are intended to be illustrative and not limiting of the various possible calibration check samples.

[0118] (Direction of Change (DOC) and Rate of Change (ROC)) Methods for the measurement of the direction and magnitude of change in concentration of tissue constituents, such as alcohol, using spectroscopy are considered within the scope of the present invention. The non-invasive measurements obtained from the present invention are essentially semi-time resolved. This allows attributes, such as alcohol concentration, to be determined as a function of time. The time resolved alcohol concentration can then be used to determine the rate and direction of change of the alcohol concentration. In addition, the change direction information can be used to partially compensate for any differences in blood and non-invasive alcohol concentrations caused by physiological dynamics. See, for example, U.S. Pat. No. 7,016,713, "Determination of Direction and Rate of Change of an Analyte," and U.S. Patent Application No. 20060167349, "Apparatus for Noninvasive Determination of Rate of Change of an Analyte," each of which is incorporated herein by reference. Various techniques have been demonstrated for enhancing the rate and direction signals. Some of these techniques include heating elements, rubrifractants, and index matching media. The present invention is not limited to a particular form of enhancement or equilibration. These enhancements are not required by the present invention, but are included for illustrative purposes only.

[0119] (Safety of the subject) Another aspect of non-invasive alcohol measurement is the safety of the subject during the measurement. To prevent measurement contamination or transfer of pathogens between subjects, it is desirable, but not necessary, to use a disposable cleaning agent and / or protective surface 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 the sampling site and / or sampling subsystem surface of each subject before measurement. In other embodiments, a disposable thin film of material such as ACLAR can be placed between the sampling subsystem and the subject before each measurement to prevent physical contact between the subject and the instrument. In other embodiments, both the cleaning and the membrane can be used simultaneously. As described in the sampling subsystem portion of this disclosure, the film can also be attached to a positioning device and then applied to the sampling site of the subject. In this embodiment, the positioning device can interface with the sampling subsystem and prevent the subject from moving during the measurement, while the membrane provides its protection.

[0120] (Local Interfering Substances) In subject measurements, the presence of local interfering substances on the sampling site is a significant concern. Many local interfering substances have spectral signatures in the near infrared region and therefore contribute significant measurement error when present. Certain embodiments of the present invention address the possibility of local interfering substances in three ways that can be used individually or together. First, a disposable cleaning agent can be used, similar to that described in the subject safety section. The use of the cleaning agent can either be at the discretion of the system operator or be a mandatory step in the measurement process. Multiple cleaning agents can also be used, which individually target different types of local interfering substances. For example, one cleaning agent can be used to remove grease and oils, while another cleaning agent can be used to remove consumer products such as cologne or perfume. The purpose of the cleaning agent is to remove local interfering substances before the attribute measurement to prevent them from affecting the accuracy of the system.

[0121] A second method for mitigating the presence of local interferents is to determine whether one or more interferents are present on the sampling site. The multivariate calibration models used in the calibration subsystem provide unique outlier metrics that yield important information about the presence of unmodeled (local or otherwise) interferents. As a result, they provide insight into the reliability of the attribute measurements. Figure 20 shows example outlier metrics from non-invasive measurements collected during a clinical study. All of the large metric values ​​(clearly separated from the majority of points) correspond to measurements where grease was intentionally applied to the subject's sampling site. These metrics do not specifically identify the cause of the outliers, but indicate that the associated attribute measurement is suspect. Exaggerated outlier metrics (e.g., values ​​above a fixed threshold) can be used to trigger a fixed response, such as repeating the measurement, applying an alternative calibration model, or a sampling site cleaning procedure. This is represented in Figure 20 as the "Spectrum Check OK" decision point.

[0122] The final local interferent mitigation method involves adapting a calibration model to include the spectroscopic signature of the local 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 will target mitigating a different interferent or class of interferents, such as oil. In some embodiments, the appropriate calibration model can be selected based on a portion of the collected spectrum that is not accounted for by the original calibration model. This portion of the spectrum is referred to as the calibration model residual. Because each local interferent or class of interferents has a unique near-infrared spectrum, the calibration model residual can be used to identify the local interferents.

[0123] The model residuals or the pure spectrum of the interferents (obtained from the stored library) can then be incorporated into the spectrum used to form the calibration. The multivariate calibration can then be reformed with the new spectrum so that the portion of the attribute signal that is perpendicular to the interferents can be determined. The new calibration model is then used to measure the attribute of interest and then reduce the impact of the local interferents on the attribute measurement accuracy. The resulting model will reduce the impact of the interferents on the alcohol measurement at the expense of measurement accuracy when the interferents are not present. This process is called calibration immunization. The immunization process is similar to the hybrid calibration formation process shown in FIG. 19, but includes an additional step of mathematically adding the spectral variance of the interferents. Note that due to the impact of the immunization process on measurement accuracy, it may be desirable to identify possible interferents for each measurement and specifically immunize against them rather than attempting to create a calibration that is immune to all possible interferents. Additional details can be found in U.S. Patent No. 20070142720, “Apparatus and methods for mitigating the effects of foreign interferents on analyte measurements in spectroscopy,” which is incorporated herein by reference.

[0124] (Advantages of alternatives to semiconductor light sources) Most light sources used in NIR and IR spectroscopy are blackbody radiators. The light emitted by a blackbody radiator is governed by Planck's law, which states that the intensity of the light emitted is a function of the wavelength and temperature of the blackbody. Figure 21 shows the 4000-8000 cm wavelength used by alcohol measuring devices. -1 (2.5~1.25μm) Range shaded, 100~33000cm -1Figure 21 shows the normalized NIR spectrum of a 1300-3000K blackbody radiator over the (100-0.3 μm) range. 1300K is a reasonable temperature for a ceramic-based blackbody light source, and 3000K is a reasonable temperature for a quartz tungsten halogen (QTH) lamp, which is often employed in spectroscopic applications. Figure 21 shows that the optical efficiency of both blackbody sources is not ideal, in that a significant amount of light is emitted at wavelengths outside the region of interest for measuring alcohol, with the ceramic light source having an optical efficiency of 58% and the QTH only 18%.

[0125] 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 into radiated light. Power and light intensity measurements on hundreds of ceramic blackbody light sources show an average of 1.1 W of light intensity at 24 W of power (4.4% electrical efficiency). When combined with an optical efficiency of 58%, the overall efficiency of a ceramic blackbody is about 2.5%. In other words, at 24 W of power, about 0.6 W of light intensity is needed to achieve the desired 4000-8000 cm2 radiation. -1 Further losses are incurred because not all of the light emitted by the light source is collected by the remainder of the optical system.

[0126] As shown by the low electrical efficiency, most of the applied power is converted into heat with losses exceeding the power requirements higher than desired. The heat generated by the blackbody light source can affect the thermal state and stability of the spectroscopic measurement device. As a result, in some cases, the device must be turned on and allowed to reach thermal equilibrium before making measurements. The equilibration time associated with blackbody light sources can range from minutes to hours, which can be disadvantageous in some cases.

[0127] Blackbody light sources exhibit aging effects as material resistance changes. From an optical perspective, there are two significant implications associated with light source degradation. First, as resistance increases, the amount of light intensity emitted decreases. In one experiment, the measured intensity over time observed for a demonstrative ceramic blackbody light source showed a 50% reduction in power over 3500 hours. Intensity degradation over time tends to be exponential in nature and may necessitate replacement of the light source at regular intervals, which may be disadvantageous within some development environments. Second, the temperature of the light source changes, modifying the distribution of light as a function of wavelength. Depending on the severity of the color temperature change, the stability of the spectroscopic device over time may be affected. Solid-state light sources do not fail critically in the same way as incandescent light bulbs, and have typical lifetimes ranging from 50,000 to 100,000 hours. As a result, solid-state light sources offer the potential for a 10-fold improvement in light source lifetime and a corresponding reduction in the need for routine maintenance over blackbody sources.

[0128] Semiconductor light sources such as diode lasers can have small emitting areas compared to their blackbody counterparts, driven by the size of the semiconductor die itself. Once photon emission is generated within the semiconductor structure, it cannot occur outside the area of ​​the die. Any non-uniformity within that area will be proportional to the size of the illumination system's output (which can be several mm depending on the application). 2 small size (typical radiating area is 0.3 mm x 0.3 mm square or 0.09 mm or more) 2 ) can be advantageous. Thus, as long as the die (or dies, if multiple semiconductors are employed) does not physically move, the spatial output will be very stable. The purpose of the subsequent spatial homogenizer is then to uniformly distribute the light emitted by the die over the entire area of ​​the illumination system output.

[0129] Another advantage of semiconductor light sources such as diode lasers, VCSELs, and LEDs is the ability to incorporate more than one dye into the same physical package. For example, additional solid-state light sources of the same type can be included to increase the light intensity at corresponding wavelengths. Such an approach allows an unprecedented level of control over both the specific wavelengths and relative intensity emitted by the illumination system. This can be used to highlight wavelengths important for a given analyte of interest, such as alcohol, while reducing the output at less important wavelengths. A set of solid-state light sources, whether all of the same type or a mixture, can be incorporated into the same package, up to hundreds, while retaining an integrated optical range consistent with application in non-invasive analyte measurements such as alcohol.

[0130] Another advantage of solid-state light sources is the ability to select which light sources are on at a given time and tune their output via voltage or current and temperature. As a result, a single illumination system can be optimized for the measurement of multiple analytes. For example, a given set of solid-state light sources can be activated when measuring alcohol in tissue. Similarly, a different set can be activated when measuring different analytes such as cholesterol or glucose.

[0131] (Methods for spatial and angular homogenization) Light homogenizers, such as optical diffusers, light pipes, and other scramblers, can be incorporated into some embodiments of the illumination / modulation subsystem 100 to provide a 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 solid-state light sources. Uniform radiance can be utilized to achieve accurate and precise measurements. See, for example, U.S. Patent No. 6,684,099, which is incorporated herein by reference.

[0132] A ground glass plate is an example of an optical diffuser. The polished surface of the plate effectively scrambles the radiation angle emanating from the solid-state light source and its transmission optics. A light pipe can be used to homogenize the intensity of the radiation so that it is spatially uniform at the output of the light pipe. In addition, a light pipe with a double bend will scramble the radiation angle. To create a 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 be directly coupled to the input of the tissue sampler or can be used in conjunction with additional transmission optics before the light is sent to the tissue sampler. See, for example, U.S. Patent Application Serial No. 09 / 832,586, "Illumination Device and Method for Spectroscopic Analysis," incorporated herein by reference.

[0133] In an exemplary embodiment, the radiation homogenizer is a light pipe. Light pipes are generally fabricated from metal, glass (amorphous), crystal, polymer, or other similar materials, or combinations thereof. Physically, a 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 91 may have various lengths depending on the shape the segment forms. The length of a segment easily varies with the intended application of the light pipe.

[0134] In an exemplary embodiment, the segments form 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. However, it is recognized that angular homogenization can be achieved in other ways. Multiple bends or non-S-shaped bends can be used. Additionally, a straight light pipe can be used, provided that the inner surface of the light pipe includes a diffuse reflective coating that covers at least a portion of the length. The coating provides angular homogenization as the light travels through the pipe. Alternatively, the inner surface of the light pipe can be modified to include indentations or "microstructures," such as micro-optical diffusers or lenses that achieve angular homogenization. Finally, a polished diffuser can be used to provide some angular homogenization.

[0135] 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 have been shown to improve spatial homogenization of the channel radiation. For example, a light pipe possessing a hexagonal cross section along its entire length provided improved spatial homogenization compared to a light pipe with a cylindrical cross section of the same length.

[0136] In addition, the cross section 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 the pipe. In some embodiments, the light pipe is a hollow structure between two ends. In these embodiments, at least one lumen or conduit may span the length of the light pipe. The lumen of a hollow light pipe generally possesses reflective properties. This reflective property aids in channeling radiation through the length of the light pipe such that radiation may be emitted at the distal end of the pipe. The inner diameter of the lumen may further possess either a smooth, diffuse, or textured surface. The surface properties of the reflective lumen or conduit aid in spatially and angularly homogenizing radiation as it travels through the length of the light pipe.

[0137] In additional embodiments, the light pipe is a solid structure. The solid core can be cover plated, coated, or clad. Again, solid structure light pipes generally provide internal reflection. This internal reflection allows radiation entering the proximal end of the solid light pipe to be guided through the length of the pipe. The guided radiation may then be emitted out the distal end of the pipe without significant loss in radiant intensity.

[0138] A faceted elliptical reflector is an example of an embodiment of the invention that produces only some of the desired characteristics in the output radiation. In the case of a faceted reflector, spatial homogenization is achieved, but not angular homogenization. In other cases, such as passing the output of a standard system through ground glass, angular homogenization is achieved, but not spatial homogenization. In embodiments such as these, where only angular or spatial homogenization (but not both) is produced, some improvement in the performance of the spectroscopic system can be expected. However, the degree of improvement would not be expected to be as great as in systems where spatial and angular homogenization of the radiation is achieved simultaneously.

[0139] Another method for creating both angular and spatial homogenization is to use an integrating sphere in the illumination system. In particular, while it is common to use integrating spheres in the detection of light from light-scattering samples, integrating spheres have not been used as part of the illumination system when attempting to measure analytes non-invasively. In practice, radiation output from an emitter can be coupled into the integrating sphere with subsequent illumination of tissue through an exit port. The emitter can also be located within the integrating sphere. An integrating sphere would provide exceptional angular and spatial homogenization, but the efficiency of this system is significantly less than other previously identified embodiments.

[0140] It is also recognized that other modifications can be made to the disclosed system to achieve the desired homogenization of light. For example, a solid state light source can be placed inside the light pipe in a sealed arrangement that would eliminate the need for a reflector. Additionally, the light pipe can be replaced with an integrator, with the light source being placed within the integrator. Additionally, the system can be used in non-infrared applications to achieve similar results in different wavelength regions depending on the type of analysis being performed.

[0141] (Description of the embodiment) In an example embodiment of the present invention (schematically depicted in FIG. 22), a non-invasive alcohol measurement system consists of 13 diode lasers used to measure 22 distinct wavelengths. Table 1 lists each diode laser and the associated target peak wavelength that will be examined during the course of a measurement.

[0142] [Table 1] In this embodiment, each diode laser is stabilized to a constant temperature. The peak wavelength of each diode laser is controlled based on the circuit shown in FIG. 5 (each diode laser has its own circuit), which also allows the diode laser to be turned on and off. The specific state (on / off) of each diode laser at a given time during the measurement is determined by a predefined Hadamard or similar encoding matrix. In an example embodiment incorporating a solid-state light source, the Hadamard matrix is ​​a pattern of on / off states versus time for each diode laser that is stored in software and implemented in electronics rather than a physical mask or chopper that would mechanically modulate the solid-state light source. This allows the on / off states stored in the software to be communicated to the electronic control circuitry of each diode laser during the measurement.

[0143] Since some of the diode lasers in Table 1 are involved in two wavelength locations, a Hadamard scheme incorporating all wavelengths may be difficult to achieve. In this case, a combination of scanning and Hadamard encoding can allow all target wavelengths to be measured. In this embodiment, all diode lasers (for those with more than one target wavelength) are tuned to their first target wavelength, and a Hadamard encoding scheme is used to achieve the associated multiplexing benefits. Diode lasers can then be tuned to their second target wavelength, and a second Hadamard encoding scheme can be used. Diode lasers with only one target wavelength can be measured in one or both groups, or can be split between the groups.

[0144] Additionally, the groups can be interleaved in time. For example, for a two second measurement, the first group can be measured in the first second and the second group in the second. Alternatively, the measurements can alternate at 0.5 second intervals over the two seconds. The measurement times do not need to be symmetric across the groups. For example, it may be desirable to optimize the signal to noise ratio by weighting the measurement times towards one or the other group. Those skilled in the art will recognize that many permutations of balancing measurement times, number of groups, balancing scan to Hadamard ratios, and interleaving are possible and contemplated in embodiments of the present invention.

[0145] In an example embodiment, the output of each diode laser is combined and homogenized using a hexagonal cross-section light pipe. In some embodiments, the light pipe may contain one or more bends to provide angular homogenization in addition to spatial homogenization. In any case, at the output of the light pipe, the emission of all the diode lasers is preferably spatially and angularly homogenized such that all wavelengths have substantially equal spatial and angular content upon introduction to the input of the sampling subsystem 200.

[0146] The homogenized light is introduced to the input of the optical probe. In an example embodiment, the input consists of 225 0.37 NA silica-silica optical fibers (called illumination fibers) arranged in a geometry that matches the cross section of the light homogenizer. The light is then transmitted to the sample interface. The light exits the optical probe and enters the sample, where a portion of the light interacts with the sample and is collected by 64 collection fibers. In an example embodiment, the collection fibers are 0.37 NA silica-silica fibers.

[0147] The optical probe output arranges the collection fibers in a geometry that matches the introduction into the homogenizer. For an example embodiment, the homogenizer is a hexagonal light pipe. The homogenizer ensures that the contents of each collection fiber contribute substantially equally to the measured optical signal. This can be important for samples such as human tissue, which can be inherently heterogeneous. The output of the homogenizer is then focused onto a photodetector. In an example embodiment, the photodetector is an extended InGaAs diode, whose output current varies with the amount of incident light.

[0148] The processing subsystem then filters and processes the current and converts it to a digital signal using a two-channel delta-sigma ADC. In an example embodiment, the processed analog detector signal is split and introduced to both ADC channels. Because the example embodiment involves a VCSEL with two measurement groups (e.g., two target wavelengths), a Hadamard transform is applied to the spectroscopic signals obtained from each group, and the subsequent transforms are combined to form an intensity spectrum. The intensity spectrum is then logarithmically transformed to base 10 before subsequent alcohol concentration determination.

[0149] Example embodiments are suitable for applications combining either the "registration" or "walk-up / generic" modalities, as well as alcohol with other analyte properties, such as substances of abuse. Additionally, any of the modalities or combinations discussed may be considered independently or may be combined with the measurement of biometric properties.

[0150] 3,245 alcohol measurements were taken from 89 individuals on five non-invasive alcohol systems measuring spectra incorporating 22 wavelengths in a "walk-up" modality. Measurements spanned a wide range of demographics and environments. FIG. 23 shows near-infrared spectroscopy measurements obtained from the study. FIG. 24 compares the non-invasive alcohol concentrations obtained from the spectroscopy measurements shown in FIG. 23 with concurrent capillary blood alcohol concentrations (BAC).

[0151] Another example embodiment is shown in Figure 39 and uses 39 wavelengths measured using 39 diode lasers. Table 2 shows the diode lasers and their target wavelengths.

[0152] [Table 2] The remaining system parameters, including the sampling subsystem, optical homogenizer, detector, and processing, are identical to the previous embodiment. Figure 25 shows 8,999 spectroscopic measurements taken from 134 individuals on six non-invasive measurement devices. Figure 26 shows the resulting non-invasive alcohol measurements for venous blood alcohol.

[0153] In some example embodiments, a calibration move can be made using a small number of measurements on samples with known analyte properties. For non-invasive alcohol measurements, each device can have a small number of measurements made on individuals with no alcohol present. Any non-zero alcohol result on the device becomes a measurement error that can be used to correct subsequent measurements on that device. The number of measurements used to estimate the correction can vary and generally depends on the correction accuracy required. In general, this process is similar to device-specific calibration that matches alcohol devices such as individually calibrated breath testers.

[0154] A similar approach can be applied to calibration maintenance. In many applications of alcohol testing, the majority of measurements are made on individuals where alcohol is unlikely to be present. For example, in workplace safety, where employees are routinely tested for alcohol, employees will be much more likely to 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 the median, or other means to filter out low frequency true alcohol events can be used to estimate the instrument correction. This can be implemented as a running median filter, a moving window, or a more sophisticated multivariate algorithm to determine the appropriate correction at a given time.

[0155] 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, and therefore departures may be made in form and detail without departing from the scope and spirit of the present invention.

[0156] (Ongoing system calibration) In order to maintain maximum accuracy and precision over operating conditions and time, it is desirable to have information about the state of the alcohol measurement device (e.g., the optical and electrical components that contribute to the measurement) immediately prior to the tissue measurement. This is called a "calibration measurement." Although current and temperature related controls are employed for certain sensing components of the system, there are a significant number of mechanical and optical error contributors that may change with time and temperature. In addition, even with controls in place, there may be errors associated with the operation of electrical components as well as factors related to surface treatments, and possible optical contamination of the probe must also be considered. Therefore, it is desirable to measure the complete optical and electrical state of the device against a known standard sample immediately prior to measuring the tissue sample of interest. The measurement of the standard sample then allows the subsequent (or preceding) tissue measurement to be corrected for the current state of the alcohol measurement device.

[0157] To obtain the calibration measurements, light from the light source / modulation subsystem (100) is delivered by the sampling subsystem (200) to the standard sample where it interacts with the standard sample. A portion of the light is collected by the sampling subsystem (200) and coupled to a photodetector in the data collection subsystem (300). One way to achieve this is to use an optical fiber that is distinctly different from that of the sampling surface (e.g., the surface where the skin tissue is measured). In this case, the light delivered to the standard sample will travel a different optical path than the light that interrogates the skin. This difference in optical path may be acceptable in some embodiments. Furthermore, in other embodiments, the optical fiber itself may serve as the standard sample (e.g., the optical fiber collects light from the light source / modulation subsystem (100) and delivers it directly to the photodetector in the data collection subsystem (300)). In some embodiments of these approaches, a gating mechanism may be applied that selects which optical path (path to the skin sampling surface or path to the calibration sample) is being measured by the photodetector at a given time. Although these approaches are acceptable in some embodiments, they are not optimal in the sense that a different path than the actual probe is measured.

[0158] Therefore, a method is needed to place a movable calibration standard with known characteristics at the tissue interface of the sampling subsystem (200) to maintain a substantially identical optical path of the light interrogating the skin tissue and the calibration standard. The calibration sample can be measured immediately prior to the tissue measurement and then removed for the actual measurement. The calibration sample can be manually inserted into the path, although an automated method for insertion and removal is preferred in some embodiments.

[0159] One such method for automatic insertion of the calibration sample would be to incorporate it into the probe head cover, or into a button that the user interacts with. The key elements of such a method would be: 1) A movable door that is in close proximity to the tissue interface with a reflective standard surface added to the back. 2) A method for moving the door out of the way to present the tissue measurement surface directly to the probe. 3) How to Return the Reflective Surface to a Rest Position It should be noted that one skilled in the art could design any number of electromechanical or mechanical mechanisms to accomplish this goal.

[0160] In a first embodiment, the movable door is covered on the underside with a suitable reflective material and slides to allow the sensing head to rotate up to the finger surface. A spring provides the necessary restoring force to return to the rest / calibration position.

[0161] In a second embodiment, a sliding button acts as a guide for a semi-flexible tape that is fixed at the bottom end. The back of the flexible tape is coated with a suitable reflective surface. Movement of the sliding button allows the tape to slide below a window opening on the face of the button, allowing the sensor to come into contact with a finger. A spring provides the restoring force required to return to the rest / calibration position. Note that alternative embodiments can be designed such that the door / button and / or calibration sample are the only moving parts while the sensing head is stationary.

[0162] Additionally, without changing the basic concept, embodiments can be enhanced with styling features and finger guides to help facilitate placement, and it should be noted that the mechanisms and additional styling features will work equally well whether the dorsal side of the finger, the palmar side of the finger, or other skin surface is presented.

[0163] 28, the system depicted in FIG. 1 can be incorporated into the starting system of any transportation vehicle (including all forms of land, water, and air travel). For example, the system can be incorporated as an electromechanical component of the ignition system, including an starter button, turning a key, or other typically used forms of driver activation of power to prepare the transportation vehicle for travel.

[0164] Such a system may be utilized to measure the presence or concentration of an analyte or biometric identifier in an individual attempting to start a transportation vehicle, where the measured information is used to modify the vehicle's subsequent electromechanical response. For example, biometric identification may be used to identify a particular driver (from a population of possible drivers) and modify the location or orientation of the driver and / or control settings, such as infotainment settings or vehicle actuator settings. In another example, as illustrated in FIG. 27, the system may be used to measure the concentration of an analyte to either enable or disable the ability to start a transportation vehicle and / or initiate alternative actions. For example, a measurement of alcohol in a motor vehicle driver above the legal threshold may limit the ability to start a transportation vehicle, but may also trigger the telematics system to provide an automatic call to a designated driver and / or alternative forms of transportation, including a taxi.

[0165] In another embodiment, the system may be integrated into a transport vehicle control system that is in continuous or near continuous contact with an operator, such as a vehicle steering wheel, handlebars, or joystick. As such, the system may take analyte and / or biometric measurements that are used to affect subsequent transport vehicle operations or trigger alternative actions, either continuously or periodically, or triggered by other control logic.

[0166] In another embodiment, the system may be integrated into a transport vehicle or facility access system (e.g., entrance doors, trunks, etc.) and thus may perform analyte and / or biometric measurements that are used to affect subsequent levels of control upon access to and / or entry to the entrance.

[0167] In alternative embodiments, the system may be incorporated into other transport vehicle subsystems, where direct contact between the operator's skin and the sampling subsystem 200 is maintained temporarily, periodically, or constantly. Slightly modified embodiments in which semi-passive contact is maintained, and embodiments in which contact is made through operator-initiated actions, are also possible. In such cases, continuous or periodic analyte and / or biometric measurements may be made that affect subsequent transport vehicle actions or trigger alternative actions.

[0168] 28, human-machine interaction between the operator and the sampling subsystem 200 can be configured to inform the intended operator of the presence of the system and the intended body part and / or location that must be coupled with the sampling subsystem to trigger a measurement. For example, the use of audible sounds and / or speech and / or lighting and / or tactile feedback can be used to educate the operator and provide positive / negative feedback on the proper measurement process and / or the results of the measurement.

[0169] An example embodiment of the invention (schematically depicted in Figures 29a-b) differs from the system depicted in Figure 22 by directly coupling discrete solid-state light sources of various wavelengths into a homogenizer made of a material that minimizes loss across all supported wavelengths, thus reducing the need for coupling mechanisms between the solid-state light sources and the homogenizer and sensing subsystem. In this embodiment, the homogenizer material, size, shape, and coating can be controlled to optimize light transmission and minimize loss while directly providing the sensor subsystem 200 emitter.

[0170] FIG. 7 depicts a system in which multiple distinct emitters are used, and in an alternative embodiment depicted in FIG. 30, a single emitter can be created using several grating zones with distinct current paths that, when driven in combination with currents, produce distinct wavelengths. By varying in time which grating combinations are driven, distinct wavelengths can be achieved in the time domain signal. In that way, multiple wavelengths can be sampled in a predetermined pattern in time. Knowledge of the sampling sequence in the detector and processor can be used to obtain spectroscopy measurements as described in subsequent embodiments.

[0171] In another embodiment, the system further includes one or more atmospheric, temperature, and relative humidity sensors, and measurements derived from these sensors are available to subsystem 400 to correct and / or improve analyte and / or biometric measurements to compensate for man-made variations due to these environmental effects and / or individual subsystem variations due to the extended system (e.g., if measurement subsystem 200 is spatially or thermally distinct from subsystem 100, or if the system emitters and detectors are temperature compensated to fixed values ​​(independent of ambient conditions) but the optical fibers, homogenizers, and couplers require temperature compensation based on ambient conditions).

[0172] When making several analyte measurements where the probability of the presence of the analyte in a population of potential operators is low, it may be advantageous to make an earlier simple measurement to first determine if any analyte is evident, and then make a subsequent measurement of the concentration of the analyte only if it is detected. This is depicted in Figure 31. For example, in the case of alcohol as an analyte, the majority of predicted automobile operators will not have alcohol present in their system when attempting to start their automobile. A presence measurement can be used to reduce the average measurement time.

[0173] In many safety applications, at least two dissimilar technology sensors must detect a signal to make a decision to activate a countermeasure. This greatly reduces the tendency for false positives due to undetected single sensor failures or errors. In similar situations, the system described in FIG. 32 can be combined to include one or more independent sensors that indicate the presence or concentration of an analyte and / or confirm a biometric measurement.

[0174] The system of Figure 22 depicts a system that utilizes discrete wavelength solid-state light sources, while the alternative embodiment depicted in Figure 33 depicts a system that utilizes a single broad spectrum blackbody source coupled to a discrete wavelength filter that passes only the intended wavelengths. Subsequent processing steps remain the same as previously shown, but unwanted system noise can be avoided in the detection and discrimination process.

[0175] For previously described system embodiments utilizing diode lasers, the ramp characteristics of these devices may vary deterministically based on the driver and compensation circuitry, as well as ambient temperature and the electromechanical properties of the devices themselves (e.g., laser grating structure, material, size, shape, and heating / cooling components). As illustrated in FIG. 34, the modulation time may be reduced by waiting until the solid-state light source intensity settles to a desired level (T2). To improve the modulation rate available for multiplexed light of various wavelengths, the a priori ramp characteristics can be compensated for in the detector logic, thus reducing the settling time (T1).

[0176] It is to be understood that both the foregoing general and detailed description are exemplary and explanatory only and are not restrictive of the invention.

[0177] For purposes of this disclosure, the term "coupled" means joining two components (electrical or mechanical) directly or indirectly to one another. Such joining may be static in nature or movable in nature. Such joining may be accomplished with the two components (electrical or mechanical) and any additional intermediate members integrally formed with one another as one unitary body, or with the two components attached to one another or the two components and any additional members. Such joining may be permanent in nature, or alternatively removable or releasable in nature.

[0178] The structure and arrangement of the diffuser as shown in the preferred and other exemplary embodiments are illustrative only. Although only a few embodiments of the present airbag assembly are described in detail in this disclosure, those skilled in the art who review this disclosure will readily appreciate that many modifications are possible (e.g., variations in the size, dimensions, structure, shape, and proportions of the various elements, parameter values, mounting arrangements, material use, orientation, etc.) without significantly departing from the novel teachings and advantages of the subject matter described in this disclosure. Accordingly, all such modifications achievable by those skilled in the art from this disclosure within the scope and spirit of the present invention are intended to be included as further embodiments of the present invention. The order or sequence of any process or method steps may be changed or rearranged according to alternative embodiments. Other substitutions, modifications, changes, and omissions may be made to the design, operating conditions, and arrangements of the preferred and other exemplary embodiments without departing from the spirit of the present application.

Claims

[Claim 1] Systems, methods, etc.

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