CA2244111C - Method and apparatus for multi-spectral analysis in noninvasive nir spectroscopy - Google Patents
Method and apparatus for multi-spectral analysis in noninvasive nir spectroscopy Download PDFInfo
- Publication number
- CA2244111C CA2244111C CA002244111A CA2244111A CA2244111C CA 2244111 C CA2244111 C CA 2244111C CA 002244111 A CA002244111 A CA 002244111A CA 2244111 A CA2244111 A CA 2244111A CA 2244111 C CA2244111 C CA 2244111C
- Authority
- CA
- Canada
- Prior art keywords
- radiation
- analyte
- wavelengths
- sample
- filter means
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 75
- 238000010183 spectrum analysis Methods 0.000 title abstract description 4
- 238000004497 NIR spectroscopy Methods 0.000 title description 2
- 230000005855 radiation Effects 0.000 claims abstract description 142
- 239000012491 analyte Substances 0.000 claims abstract description 122
- 230000003595 spectral effect Effects 0.000 claims description 47
- 210000004369 blood Anatomy 0.000 claims description 43
- 239000008280 blood Substances 0.000 claims description 43
- 230000003287 optical effect Effects 0.000 claims description 40
- 238000010521 absorption reaction Methods 0.000 claims description 39
- 238000012546 transfer Methods 0.000 claims description 28
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 27
- 239000008103 glucose Substances 0.000 claims description 27
- 238000000862 absorption spectrum Methods 0.000 claims description 19
- 238000001514 detection method Methods 0.000 claims description 19
- 230000002238 attenuated effect Effects 0.000 claims description 18
- 238000004458 analytical method Methods 0.000 claims description 17
- 238000004422 calculation algorithm Methods 0.000 claims description 14
- 230000007935 neutral effect Effects 0.000 claims description 10
- 238000002329 infrared spectrum Methods 0.000 claims description 8
- 230000001678 irradiating effect Effects 0.000 claims description 7
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 230000002596 correlated effect Effects 0.000 claims description 3
- 230000000875 corresponding effect Effects 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 150000002632 lipids Chemical class 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims 1
- 239000000523 sample Substances 0.000 description 74
- 238000005259 measurement Methods 0.000 description 43
- 239000000470 constituent Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000002609 medium Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 230000036961 partial effect Effects 0.000 description 7
- 239000012736 aqueous medium Substances 0.000 description 6
- 230000002452 interceptive effect Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 5
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- 238000012545 processing Methods 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 230000002708 enhancing effect Effects 0.000 description 3
- 238000002839 fiber optic waveguide Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000012417 linear regression Methods 0.000 description 3
- 238000000491 multivariate analysis Methods 0.000 description 3
- NJPPVKZQTLUDBO-UHFFFAOYSA-N novaluron Chemical compound C1=C(Cl)C(OC(F)(F)C(OC(F)(F)F)F)=CC=C1NC(=O)NC(=O)C1=C(F)C=CC=C1F NJPPVKZQTLUDBO-UHFFFAOYSA-N 0.000 description 3
- 238000000513 principal component analysis Methods 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- VNQLBSAIKVNHFM-UHFFFAOYSA-N [W].[Hg] Chemical compound [W].[Hg] VNQLBSAIKVNHFM-UHFFFAOYSA-N 0.000 description 2
- 238000003491 array Methods 0.000 description 2
- 238000013528 artificial neural network Methods 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 238000005229 chemical vapour deposition Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 210000000245 forearm Anatomy 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000010238 partial least squares regression Methods 0.000 description 2
- 238000012628 principal component regression Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000036548 skin texture Effects 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000036962 time dependent Effects 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 1
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical compound [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012569 chemometric method Methods 0.000 description 1
- 238000007621 cluster analysis Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 210000000624 ear auricle Anatomy 0.000 description 1
- 238000000295 emission spectrum Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940056932 lead sulfide Drugs 0.000 description 1
- 229910052981 lead sulfide Inorganic materials 0.000 description 1
- XCAUINMIESBTBL-UHFFFAOYSA-N lead(ii) sulfide Chemical compound [Pb]=S XCAUINMIESBTBL-UHFFFAOYSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000013178 mathematical model Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003909 pattern recognition Methods 0.000 description 1
- 230000037368 penetrate the skin Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229910052594 sapphire Inorganic materials 0.000 description 1
- 239000010980 sapphire Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000013179 statistical model Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/14—Devices for taking samples of blood ; Measuring characteristics of blood in vivo, e.g. gas concentration within the blood, pH-value of blood
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/314—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry with comparison of measurements at specific and non-specific wavelengths
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N21/3577—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light for analysing liquids, e.g. polluted water
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N21/359—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using near infrared light
Abstract
A method and apparatus are described for determining the concentration of an analyte present in a sample using multi-spectral analysis in the near infrared range. Incident radiation containing a plurality of distinct, nonoverlapping regions of wavelengths in the range of approximately 1100 to 3500 nm is used to scan a sample. Diffusively reflected radiation emerging from the sample is detected, and a value indicative of the concentration of the analyte is obtained using an application of chemometrics techniques. Information obtained from each nonoverlapping region of wavelengths can be cross-correlated in order to remove background interferences.
Description
WO 97128438 PCTlUS97/01370 METHOD AND APPARATUS FOR MULTI-SPECTRAL
~ ANALYSIS IN NONINVASIVE NIR SPECTROSCOPY
technical Field:
The present invention relates to a method and apparatus for determining the concentration of a target analyte in a sample using multi-spectral analysis. The invention finds application in a wide range of chemical analyses, particularly in noninvasive spectrophotometric analysis of blood analytes.
Background of the Invention:-The measurement of the concentration of blood constituents finds application in a variety of procedures for the diagnosis and treatment of conditions and disease in human subjects. One important application is in the measurement of blood glucose. Specifically, the concentration of blood glucose should be monitored on a periodic basis in persons suffering from diabetes, and in insulin-dependent or Type I diabetes, it is often necessary or desirable to monitor blood glucose several times a day. Further, the measurement of blood cholesterol concentrations provides important information in the treatment or prevention of persons suffering from coronary artery disease, and the measurement of other organic blood analytes, such as bilirubin and alcohol, ' is important in various diagnostic contexts.
The most accurate and widely practiced method of obtaining blood analyte concentrations involves the extraction of blood from a patient, which blood is then analyzed, either in a laboratory using
~ ANALYSIS IN NONINVASIVE NIR SPECTROSCOPY
technical Field:
The present invention relates to a method and apparatus for determining the concentration of a target analyte in a sample using multi-spectral analysis. The invention finds application in a wide range of chemical analyses, particularly in noninvasive spectrophotometric analysis of blood analytes.
Background of the Invention:-The measurement of the concentration of blood constituents finds application in a variety of procedures for the diagnosis and treatment of conditions and disease in human subjects. One important application is in the measurement of blood glucose. Specifically, the concentration of blood glucose should be monitored on a periodic basis in persons suffering from diabetes, and in insulin-dependent or Type I diabetes, it is often necessary or desirable to monitor blood glucose several times a day. Further, the measurement of blood cholesterol concentrations provides important information in the treatment or prevention of persons suffering from coronary artery disease, and the measurement of other organic blood analytes, such as bilirubin and alcohol, ' is important in various diagnostic contexts.
The most accurate and widely practiced method of obtaining blood analyte concentrations involves the extraction of blood from a patient, which blood is then analyzed, either in a laboratory using
-2-highly accurate and sensitive assay techniques, or by the use of less accurate self-testing methods. In particular, traditional blood glucose monitoring methods require the diabetic to draw a blood sample (e.g., by a finger-tip lance) for each test and to read the glucose level using a glucometer (a spectrophotometer that reads glucose concentrations) or a colorimetric calibration method. such invasive blood extractions create a painful and tedious burden to the diabetic and expose the diabetic to the possibility of infection, particularly in light of the frequency of testing which is necessary.
These considerations can lead to an abatement of the monitoring process by the diabetic.
Accordingly, there' is a rE~cognized need in the art for a simple and accurate method and device 'for noninvasively measuring blood analyte concentration, particularly in the context of blood glucose monitoring by diabetics. one approach to the problem involves the use of traditional methods of near infrared (near-IR, or "NIR") analysis, wherein the measurement of absorbance at one or more specific wavelengths 1 '~ is used to extract analyte-specific information from a given sample.
Near-IR absorbance spectra of liquid samples contain a large amount of information about the various organic constituents of the sample.
Specifically, the vibrational, rotatianal and stretching energy associated with organic molecular structures (e.g., carbon-carbon, carbon-hydrogen, carbon-nitrogen and nitrogen-hydrogen chemical bonds) produces perturbations in the near-IR region which can be detected and related to the concentration of various organic constituents present in the sample.
However, in complex sample matrices, near-IR spectra also contain an appreciable amount of interferences, due in part to similarities of structure amongst analytes, relative levels of analyte concentration, interfering relationships between analytes and the magnitude of electronic and chemical "noise" inherent " in a particular system. Such interferences reduce the efficiency and precision of measurements obtained using near-IR spectrometry to determine the concentration of liquid sample analytes. However, a number of near-IR devices~and methods have been described to provide noninvasive blood analyte 1o determinations.
U.S. Patent No. 5,360,004 to Purdy et al.
describes a method and apparatus for the determination of blood analyte concentrations, wherein a body portion is irradiated with radiation containing two or more distinct bands of continuous-wavelength incident radiation. Purdy et al. emphasize filtration techniques to specifically block radiation at the two peaks in the NIR absorption spectrum for water, occurring at about 1440 and 1935 nm. Such selective blocking is carried out in order to avoid a heating .effect that may be due to the absorption of radiation by water in the body part being irradiated.
By contrast, U.S. Patent No. 5,267,152 to Yang et al. describes noninvasive devices and techniques for measuring blood glucose concentration using only the portion of the IR spectrum which contains the NIR water absorption peaks (e.g., the "water transmission window," which includes those wavelengths between 1300 and 1900 nm). optically controlled light is directed to a tissue source and then collected by an integrating sphere. The collected light is analyzed and blood glucose ' concentration calculated using a stored reference calibration curve.
' 35 Devices have also been described for use in determination of analyte concentrations in complex samples.
These considerations can lead to an abatement of the monitoring process by the diabetic.
Accordingly, there' is a rE~cognized need in the art for a simple and accurate method and device 'for noninvasively measuring blood analyte concentration, particularly in the context of blood glucose monitoring by diabetics. one approach to the problem involves the use of traditional methods of near infrared (near-IR, or "NIR") analysis, wherein the measurement of absorbance at one or more specific wavelengths 1 '~ is used to extract analyte-specific information from a given sample.
Near-IR absorbance spectra of liquid samples contain a large amount of information about the various organic constituents of the sample.
Specifically, the vibrational, rotatianal and stretching energy associated with organic molecular structures (e.g., carbon-carbon, carbon-hydrogen, carbon-nitrogen and nitrogen-hydrogen chemical bonds) produces perturbations in the near-IR region which can be detected and related to the concentration of various organic constituents present in the sample.
However, in complex sample matrices, near-IR spectra also contain an appreciable amount of interferences, due in part to similarities of structure amongst analytes, relative levels of analyte concentration, interfering relationships between analytes and the magnitude of electronic and chemical "noise" inherent " in a particular system. Such interferences reduce the efficiency and precision of measurements obtained using near-IR spectrometry to determine the concentration of liquid sample analytes. However, a number of near-IR devices~and methods have been described to provide noninvasive blood analyte 1o determinations.
U.S. Patent No. 5,360,004 to Purdy et al.
describes a method and apparatus for the determination of blood analyte concentrations, wherein a body portion is irradiated with radiation containing two or more distinct bands of continuous-wavelength incident radiation. Purdy et al. emphasize filtration techniques to specifically block radiation at the two peaks in the NIR absorption spectrum for water, occurring at about 1440 and 1935 nm. Such selective blocking is carried out in order to avoid a heating .effect that may be due to the absorption of radiation by water in the body part being irradiated.
By contrast, U.S. Patent No. 5,267,152 to Yang et al. describes noninvasive devices and techniques for measuring blood glucose concentration using only the portion of the IR spectrum which contains the NIR water absorption peaks (e.g., the "water transmission window," which includes those wavelengths between 1300 and 1900 nm). optically controlled light is directed to a tissue source and then collected by an integrating sphere. The collected light is analyzed and blood glucose ' concentration calculated using a stored reference calibration curve.
' 35 Devices have also been described for use in determination of analyte concentrations in complex samples.
-3-WO 97/28438 PC'f/US97/0I370 For example, U.S. Patent No. 5,242,602 to Richardson et al. describes methods for analyzing aqueous systems to detect multiple active or inactive water treating components. The methods involve determination of the absorbance or emission spectrum of the components over the range of 200 to 2500 nm, ' and application of chemometrics algorithms to extract segments of the spectral data obtained to quantify multiple performance indicators.
U.S. Patent No. 5,252,829 to Nygaard et al.
describes a method and apparatus for measuring the concentration of urea in a milk sample using an infrared attenuation measuring technique.
Multivariate techniques are carried out to determine spectral contributions of known components using partial least squares algorithms, principal component regression, multiple linear regression or artificial neural network learning. Calibration is carried out by accounting for the component contributions that block the analyte signal of interest. Thus, Nygaard et al. describe a technique of measuring multiple analyte infrared attenuations and compensating for the influence of background analytes to obtain a more accurate measurement.
U.S. Patent No. 4,975,581 to Robinson et al.
describes a method and apparatus for determining analyte concentration in a biological sample based on a comparison of infrared energy absorption (i.e., differences in absorption at several wavelengths) between a known analyte concentration and a sample.
The comparison is performed using partial least squares analysis or other multivariate techniques.
U.S. Patent No. 4,882,492 to Schlager describes a method and apparatus for non-invasive determination of blood analyte concentrations.
Modulated IR radiation is directed against a tissue sample (e. g., an ear lobe) and either passed through
U.S. Patent No. 5,252,829 to Nygaard et al.
describes a method and apparatus for measuring the concentration of urea in a milk sample using an infrared attenuation measuring technique.
Multivariate techniques are carried out to determine spectral contributions of known components using partial least squares algorithms, principal component regression, multiple linear regression or artificial neural network learning. Calibration is carried out by accounting for the component contributions that block the analyte signal of interest. Thus, Nygaard et al. describe a technique of measuring multiple analyte infrared attenuations and compensating for the influence of background analytes to obtain a more accurate measurement.
U.S. Patent No. 4,975,581 to Robinson et al.
describes a method and apparatus for determining analyte concentration in a biological sample based on a comparison of infrared energy absorption (i.e., differences in absorption at several wavelengths) between a known analyte concentration and a sample.
The comparison is performed using partial least squares analysis or other multivariate techniques.
U.S. Patent No. 4,882,492 to Schlager describes a method and apparatus for non-invasive determination of blood analyte concentrations.
Modulated IR radiation is directed against a tissue sample (e. g., an ear lobe) and either passed through
-4 -the tissue or impinged on a skin surface where it is spectrally modified by a target analyte (glucose).
The spectrally modified radiation is then split, ' wherein one portion is directed through a negative correlation cell and another through a reference cell.
Intensity of the radiation passing through the cells are compared to determine analyte concentration in the sample.
U.S. Patent No. 4,306,152 to Ross et al.
describes an optical fluid analyzer designed to minimize the effect of background absorption (i.e., the overall or base level optical absorption of the fluid sample) on the accuracy of measurement in a turbid sample or in a liquid sample which is otherwise difficult to analyze. The apparatus measures an optical signal at the characteristic optical absorption of a sample component of interest and another signal at a wavelength selected to approximate background absorption, and then subtracts to reduce the background component of the analyte-dependent signal.
The accuracy of information obtained using the above-described methods and devices is limited by the spectral interference caused by background, i.e., non-analyte, sample constituents that also have absorption spectra in the near-IR range. Appreciable levels of background noise represent an inherent system limitation, particularly when very little analyte is present. In light of this limitation, attempts have been made to improve signal-to-noise ratios, e.g., by avoiding water absorption peaks to enable the use of increased radiation intensity, by ' reducing the amount of spectral-information to be analyzed, or by using subtraction or compensation techniques based on an approximation of background absorption. Although such techniques have provided some improvement, there remains a need to provide a _5_ method and apparatus capable of rendering a more precise determination of the concentration of analytes in a liquid matrix, particularly in the context of blood glucose monitoring. ' Disclosure of the Invention Accordingly, it is a primary object of the invention to address the above-described needs in the art, by providing a method of determining the concentration of an analyte present in a sample having a varying background matrix and possibly having substantial component interferences as well. The method accounts for the similarity of structures among various components present in the sample, the I5 relative magnitude of the analyte concentration and spectral interferences provided by various sample components and instrumentation variances.
The method generally involves: (2) identifying several distinct, nonoverlapping regions of wavelengths in the near-IR range, which have high correlation to the concentration of the analyte; (2) irradiating a sample with incident radiation containing those regions in order to obtain radiation that has been spectrally attenuated as a result of interaction with sample constituents; (3) detecting the spectrally attenuated radiation; (4) measuring the intensity of the spectrally attenuated radiation at a wavelength in nonoverlapping regions of wavelengths;
and (5) correlating the measurements to obtain a value indicative of the concentration of the analyte.
It is also an object of the invention to provide a spectrophotometric apparatus for determining the concentration of an analyte present in a sample having a varying background matrix and substantial component interferences. The apparatus is used in a multi-spectral analysis to obtain spectral information containing analyte-specific signals as well as signals _7_ related to instrument background noise and interfering spectral information.
Chemometrics techniques are used to configure filter elements capable of enhancing the correlation of analyte-specific information with the concentration of the analyte and to derive system algorithms capably: of determining analyte concentration values.
In one aspect of the invention, an apparatus is provided which includes a specialized optic;al transfer cell that is capable of enhancing the correlation of analyte-specific information with the concentration of the analyte. The specialized optical transfer cell contains a positive correlation filter adapted to selectively emphasize wavelengths having high correlation witri the concentration of a selected analyte. The emphasized wavelengths are communicated to a means for receiving the information and converting the same into a signal representative of the intensity of the wavelength.
According to a first aspect of the invention, there is provided an apparatus for determining the concentration of an analyte in a sample, comprising: (a) means for-irradiating the sample with incident radiation containing a plurality of distinct, 1'~ nonoverlapping spectral regions of wavelengths in the near-infrared spectrum; (b) means for collecting reflected radiation emergin~~ from the sample and directing said reflected radiation into first And second light paths, wherein the first light path comprises radiation from a first spectral region of wavelengths; (c) first filter means disposed in the first light path, wherein the first filter means is capable of selectively passing radiation having substantially no correlation with the concentration of the analyte; (d) first detection means for receiving selectively passed radiation emerging from the first filter means and for converting the same into a signal representative of the intensity of said radiation; (e) adjustable filter rneans disposed in the second light path, wherein the adjustable filter means attenuates the intensitar of radiation in the second light path; (f) principal analyte 2'_i filter means capable of receiving attenuai.ed radiation emerging from the adjustable filter means, and selectively passing one or more independent wavelengths therefrom, wherein the one or more indepf:ndent wavelengths are specifically correlated with the concentration of the analyte; (g;9 second filter means capable of receiving the one or more independent wavelengths emerging from the principal analyte filter means and 3() attenuating the intensity of each indepE:ndent wavelength; and (h) second detection means for receiving the attenuated independent wavelengths emerging from the second filter means and converting thf~~ detected wavelengths into a signal representative of the intensity of said wavelengths.
-7a-According to a second aspect of the invention, there is provided an apparatus for determining the concentration of an analyte in a sample, comprising: (a) a source capable of emitting radhation containing a plurality of distinct, nonoverlapping spectral regions in the near-infrared spectrum; (b) means for dividing radiation emitted by s the source of part (a) into first and second beam paths; (c) means for irradiating the sample with the radiation in the first beam path, thereby providing reflected radiation; (d) means for collecting the reflected radiation emerging from the sample and directing said reflected radiation into a reflected light path; (e) a first optical transfer cell disposed in the reflected light path, said first cell comprising first positive correlation filter means having absorption characteristics adapted to accept the reflected radiation and emphasize one or more wavelengths from the reflected r<3diation, wherein said one or more wavelengths have high correlation with the concentration of the analyte in the sample; (f) means for receiving the one or more emphasized wavelengths from the first optical transfer cell and for converting the same into aignals representative of the intensity of said emphasized 1:i wavelengths; (g) a second opkic~al transfE~r cell disposed in the second beam path, said second cell comprising neutral density filter means having absorption characteristics sufficient to attenuate the intensity of thE: radiation from the second beam path equally over a selected range of near-infrared wavelengths; (h) means for receiving attenuated radiation from the second optical transfer cell and for converting the same into signals representative of the intensity thereof; and (i) means for calculating the concentration of the analyte in the sample using the signals generated by means (f) and (h) .
According to a third aspect of the invention, there is provided an apparatus for determining the concentration of an analyte in a sample, comprising: (a) a source capable of emitting radiation containing a plurality of distinct, nonoverlapping 2.'i spectral regions of wavelength in the rear-infrared spectrum; (b) means for dividing radiation emitted by the source into first and second beam paths; (c) means for irradiating the sample with the radiation in the first beam path, thereby providing reflected radiation; (d) means for collecting the reflected radiation emerging from the sample and directing said reflected radiation into a reflected light path; (e) a first optical transfer cell disposed in the reflected light path, said first call comprising first positive correlation filter means having ak>sorption characteristics adapted to accept the reflected radiation and emphasize one or more wavelengths from the reflected radiation, wherein said one or more wavelengths have high correlation with the concentration of the analyte in the sample; (f) means for receiving the one or more emphasized wavelengths from the first -7b-optical transfer cell and for converting the same into signals representative of the intensity of said emphasized wavelengths; (g) a second optical transfer cell disposed in the second beam path, said second cell comprising a second positive correlation filter means having absorption characteristics identical to those of the first positive correlation filter means; (h) rneans for receiving attenuated radiation from the second optical transfer cell and for converting the same into signals representative of the intensity thereof; and (i) means for calculating the concentration of the analyte in the sample using the signals generated by means (f) and (h).
Brief Description of the Fictures Figure 1 is a diagramrraatic representation of an apparatus constructed according to the invention.
Figure 2 is a diagrammatiic representation of a correlation spectrometer apparatus constructed according to the invention.
Figure 3 is a graph illustrating time dependent scans taken during an In vivo glucose tolerance study.
Figure 4 depicts in graph form the results obtained from a noninvasive determination of blood glucras~e concentration conducted using the method of the invention.
Modes for Carrvina Out the Invention Before the invention is described in detail, it is to be understood that this invention is not WO 97/28438 fCT/US97/01370 limited to the particular component parts of the devices or methods described, as such may vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an analyte'° includes mixtures of analytes, reference to "an optical transfer cell"
includes two or more optical transfer cells, "a means for ref lectively transmitting radiation" includes two or more such means, "a wavelength" includes two or more wavelengths, "a chemometrics algorithm" includes two or more algorithms, and the like.
In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings:
"Chemometrics" relates to the application of mathematical, statistical and pattern recognition techniques in chemical analysis applications. See, e.g., Brown et al. (1990) Anal. Chem. 62:84-101.
Chemometrics is practiced herein in the context of developing and using noninvasive diagnostic instrumentation that employs advanced signal processing and calibration techniques. Signal processing is used to improve the accessibility of physically significant information in analytical signals. Examples of signal processing techniques include Fourier transformation, first and second derivatives, and digital or adaptive filtering. ' In the context of chemometrics, "calibration" refers to the process of relating data ' measurements to a chemical concentration for the purpose of quantification. Particularly, statistical _g_ WO 97128438 PCTl1JS97/01370 calibrations using chemometric methods can be used to extract specific information from a complex set of data. Such methods of calibration include linear ' regression, multiple-linear regression, partial linear regression, and principal components analysis. In other applications, calibrations can be carried out using artificial neural networks, genetic algorithms and rotated principal components analysis.
Instrumentation that detects information for one or more constituents in a complex chemical matrix must rely upon analysis algorithms (such as those derived using chemometrics) in order to reveal information that is specific for one or more chemical constituent. Chemometrics techniques can be used to compare unknowns with calibrated standards and data bases to provide advanced forms of cluster analysis, and to extract features from an unknown sample that can be used as information in statistical and mathematical models.
"Principal components analysis" (PCA) is one method of data reduction which can be performed in the application of chemometric techniques to spectroscopic measurement of chemical analytes in a complex matrix.
PCA is used to reduce the dimensionality of a large number of interrelated variables while retaining the information that distinguishes one component from another. This reduction is effected using an eigenvector transformation of an original set of interrelated variables (e. g., an absorption spectrum}
into a substantially smaller set of uncorrelated principal component (PC) variables that represents most of the information in the original set. The new set of variables is ordered such that the first few retain most of the variation present in all of the original variables. See, e.g., Jolliffe, L.T., Principal Component Analysis, Sprinter-Verlag, New York (1986). More particularly, each PC is a linear WO 97/28438 PCTlUS97/01370 combination of all the original measurement variables.
The first is a vector in the direction of the greatest variance of the observed variables. The succeeding PCs are chosen to represent the greatest variation of ' the measurement data and to be orthogonal to the previously calculated PC. Therefore, the PCs are ' arranged in descending order of importance.
The term ''weighting constant" includes the wavelength coefficients of partial least squares regression and/or principal components regression, or any constant obtained from any statistical calibration that can be used to calculate values (such as analyte concentration) for unknown samples. A "wavelength weighting factor" is an embodiment of a weighting constant which is used in the construction of an optical filter means capable of emphasizing wavelength-specific information from spectral data.
The wavelength-specific information can be used to determine desired values relating to the sample undergoing analysis (e.g., analyte concentration). A
wavelength weighting factor can be embodied as a particular filter density (e.g., neutral or wavelength-specific), filter thickness, or the like, such parameters having been determined using the above-described statistical calibration techniques.
The term "optical transfer cell" encompasses any optically active element that partially absorbs incident radiation in the visible, ultraviolet, or infrared spectral regions, wherein the partial absorption is selective with respect to wavelength.
For the purposes of the present invention, an optical transfer cell generally comprises an optical filter means having absorption characteristics that were derived from a partial least squares or principal components regression analysis. The optical filter means is used to selectively emphasize wavelengths having high correlation with a selected analyte concentration. "High correlation," or "close correlation" refers to the quantitative association between the absorption spectrum at a particular wavelength and a particular analyte concentration, wherein the two variables have a correlation coefficient (r) of 0.9 or higher.
A "positive correlation filter" is an optical filter means having an absorption spectrum sufficient to emphasize radiation of particular wavelengths corresponding to the target analyte and not to other absorbing analytes. Thus, the positive correlation filter provides an optimal transfer function that is highly correlated with the analyte concentration in the sample being measured. An ideal positive correlation filter would correlate perfectly with a target analyte (i.e., the correlation coefficient r would be +1.0), and not correlate at all with all other interfering absorbing analytes in a particular sample (r would be 0.0). The synthesis of positive correlation filters is carried out herein using chemometric techniques to determine appropriate wavelength weighting factors.
A "neutral density filter" refers to a standard optical filter means having a flat absorption spectrum. A neutral density filter can be used in concert with correlation filters in a filter system to provide a weighting factor to attenuate absorbances due to the analyte at selected wavelengths and further improve the accuracy of the correlation provided by the system. A neutral density filter can have an absorption spectrum sufficient to attenuate radiation equally at all wavelengths in the range of interest.
- As used herein, an "aqueous medium'r encompasses any substrate relating to, made from, or comprising water. Thus, an aqueous medium includes media wherein water is the major component, i.e., is present in an amount of at least about 50%, as well as WO 97128438 PCT/US9?/01370 wherein water is a solvent but is present in amounts of less than about 50%. Aqueous mediums are specifically defined herein to include mammalian tissue. ' The term "blood analyte" refers to a blood constituent that is absorbing in the near-IR range, "
the measurement of which is useful in patient monitoring or in the provision of health care.
As used herein, the term "near infrared°' or "near-IR" encompasses radiation in a spectrum ranging from approximately 660 nm to 3500 nm, but typically in the range of approximately 1050 to 2850 nm, and mare typically in the range of approximately 1100 to about 2500 nm.
The term "background absorption" relates to the overall or base level of optical absorption of an aqueous sample which is to be analyzed, from which the absorption of a selected constituent departs at one or more characteristic wavelengths to an extent indicative of the concentration of the selected constituent. When the level of background absorption is high in relation to the characteristic absorption of the selected constituent, such as in complex aqueous media where numerous interfering constituents are found, accurate measurement of the magnitude of a slight change in the absorption at the characteristic wavelength of a constituent of interest requires application of the chemometrics techniques described herein. This is particularly so in applications wherein the overall concentration of the constituent of interest is low relative to the aqueous medium, e.g., in the measurement of blood analytes.
General Methods A spectrophotometric method is provided for determining the concentration of an analyte in a liquid sample using near-IR radiation. In contrast to WO 97/28438 PCT/US97/013'70 prior techniques, the present method uses all of the spectral information contained in the near-IR region in order to obtain a set of measurements that can be used to determine an analyte concentration with a heightened degree of accuracy.
The method includes the steps of (1) selecting several distinct, nonoverlapping regions of wavelengths in the near-IR, wherein each region defines a spectral range, (2) irradiating a sample using near-IR light containing the selected spectral ranges to obtain spectrally modified radiation which has been attenuated, (3) collecting and measuring the intensity of the spectrally-attenuated radiation at one or more wavelengths contained within each of the selected spectral ranges, and (4) correlating those measurements to obtain a value indicative of analyte concentration.
Spectral information obtained using this method can be subjected to a combination of mathematical transformations to arrive at a precise analyte concentration value. For example, standard statistical techniques, such as partial least squares (PLS} analysis, or principal components regression (PCR) analysis, can be used to correlate the absorbance of radiation at specific wavelengths to analyte structure and concentration. PLS techniques are described, for example, in Geladi et al. (1986) Analytica Chimica Acta 185:1-17. For a description of PCR techniques, reference may be had to Jolliffe, L.T., Principal Component Analysis, Sprinter-Verlag, New York (2986).
Accordingly, in determining blood analyte - concentration from a body tissue sample, one method involves the selection of three nonoveriapping regions of wavelengths from the near IR range spanning 1100 to 3500 nm; specifically, a first regi-on spanning 1100 to 1350 nm, a second region spanning 1430 to 1450 nm or 1930 to 1950 nm, and a third region spanning 2000 to 2500 nm, wherein each region defines a "spectral range." The first region contains wavelengths in which proteins and other cellular components exhibit dominant spectral activity, the second region is dominated by the absorption spectrum of water, and the third region contains wavelengths in which organic analyte molecules exhibit significant spectral activity. These constituents also contribute to the absorption spectra in those regions where they are not the dominant species. Accordingly, the spectrally attenuated radiation obtained from each region contains a large amount of interrelated information that must be reduced using statistical methods to obtain analyte-specific information.
The invention also involves the use of signal processing to improve the accessibility of physically significant information in the analytical signals. The intensity values of signals obtained at particular wavelengths can thus be processed to reduce the effect of instrumentation noise. The processed signals are then subjected to multivariate analysis using known statistical techniques.
The PCA method of data reduction is one preferred method used in the practice of the invention to reduce the dimensionality of a large number of interrelated variables while retaining information that distinguishes one component from another. Data reduction is carried out using an eigenvector transformation of an original set of interrelated variables (e.g., the absorption spectrum) into a substantially smaller set of uncorrelated principal component (PC) variables that represents most of the information in the original set. The new set of variables is ordered such that the first few retain most of the variation present in the original set.
WO 97!28438 PCT/US97/01370 The principal component vectors can be transformed by orthogonal rotation against an average value for the absorbance to obtain both a known ' wavelength and the relative value of the absorbance at that wavelength which is attributable to the analyte.
' By performing this analysis on information obtained from each of the three spectral regions, cross-correiating the principal component vectors via a linear algorithm, and using subtractive methods to remove the effect of interfering analytes, values are obtained which can be used in a system algorithm to determine the concentration of the analyte.
Multivariate techniques are used to provide a model that relates the intensity of radiation at specific wavelengths in each spectral region to analyte concentrations in a particular sample matrix, e.g., body tissue. The model is constructed using two sets of exemplary measurements that are obtained simultaneously, the first set of measurements, the "prediction set," comprising spectral data, e.g., radiation intensity at selected wavelengths, and the second set of measurements, the "calibration set,"
comprising highly accurate analyte concentrations that have been determined using invasive sampling techniques. The procedure is carried out over a range of anaiyte concentrations to provide calibration and prediction data sets.
Measurements obtained in both the calibration set and the prediction set are subjected to multivariate analysis, such as by the use of commercially available multivariate model developing software programs, to provide an initial model. The initial model is applied to the prediction data to derive analyte concentration values that can be compared to the values obtained by the invasive techniques. By iteratively performing the above steps, a refined model is developed which can be used WO 97!28438 PCT/I1S97101370 to establish a system algorithm for use in analyzing data obtained by the methods of the invention.
The above-described multivariate techniques can also be used to design an optically active element "
capable of enhancing correlation of spectral information with analyte concentration, e.g., a positive correlation filter system. Particularly, the solutions obtained using multivariate analysis can be used to determine optical parameters, such as absorption characteristics, for positive correlation filter systems.
In the practice of the invention, non-analyte specific information from the various nonoverlapping spectral regions is also used, for example, to normalize each spectral scan, to subtract background and base line interferences, or to provide signal values used to detect an inaccurate measurement.
When determining a blood analyte concentration in a body tissue sample, measurements taken in the spectral range spanning approximately 1320 - 1340 nm provide a highly reflected, unattenuated, signal, as there are no major absorption bands present in the region. By collecting and measuring the intensity of radiation in that range, a value is obtained which can be used to estimate the actual intensity of the near-IR light used to irradiate the sample. The value can be used to normalize each individual scan and to correct for fluctuations in the intensity of the light source which could effect the accuracy of analyte concentration values obtained using the method of the invention.
Additionally, measurements taken in the spectral ranges spanning approximately 1430 - 1450 nm and approximately 1930 - 1950 nm provide substantially non-reflected, highly attenuated, signals, as a result WO 97!28438 PCT/US9710I370 of the two dominant absorption peaks occurring at about 1440 and 1935 nm in the near-IR absorption spectrum for water. By collecting and measuring the intensity of radiation in one or both of those ranges, a value is obtained which can be used to estimate the intensity of near-IR light that is not totally absorbed by the irradiated sample. The value can be used to subtract background or base-line information from the analyte-specific signals obtained in other regions and/or to provide an internal reference to detect inaccurate measurements. The value can be subtracted from each spectral measurement obtained using the present method in order to correct for the pedestal effect caused by specular reflection which varies with skin texture and age.
Measurements of substantially unattenuated signals obtained from a first region (e.g., the spectral range spanning approximately 1320 - 1340 nm) and measurements of highly attenuated signals obtained from a second region (e. g., the spectral ranges spanning approximately 1430 - 1450 nm and approximately 1930 - 1950 nm) can also be used to compare diffusely reflected radiation with specular radiation. If the signals in the two regions have relatively comparable values, it is likely that most of the radiation used to irradiate the tissue sample was reflected from the skin surface, and thus failed to penetrate the skin to interact with the blood anaiytes. This information can be used to identify ineffective measurements arising from a failure to obtain a proper instrumentation scan of the tissue sample.
The method of the invention can be carried out using a number of spectrophotometer configurations. Referring now to Figure 1, one particular apparatus for determining the concentration of an analyte in a liquid sample is generally WQ 97!28438 PCT/US97/01370 indicated at 10. The apparatus includes a radiation source 12 which provides a plurality of distinct, nonoverlapping regions of wavelengths in the approximate range of 600 to approximately 3500 nm. A ' number of suitable radiation sources are known in the art, such as incandescent light sources directed "
across interference filters, halogen light sources, modulated by an associated chopper wheel, laser light sources, laser diode arrays, or high speed light-20 emitting diode (LED) arrays. In one particular apparatus, the radiation source 12 provides radiation at three distinct regions of wavelengths, specifically a first region of wavelengths in the near-IR, typically in the range of approximately 1100 to 1350 nm, a second region generally in the range of approximately 1930 to 1950 nm, and a third region typically in the range of approximately 2000 to 3500 nm.
The apparatus 10 also includes sample 2o interface optic means 14 which launches incident radiation from the radiation source into contact with a sample medium 16 containing an analyte. After contacting the sample medium, spectrally modified radiation emerging from the sample as diffusively reflected light is collected and delivered to a first lens system i8, whereby the light is directed into first and second light paths, respectively indicated at 20 and 22. The first lens system 18 can comprise a partial reflected mirror configuration such as those known in the art.
In various configurations, the sample interface optic means 14 can be designed to enable the close interface of the apparatus l0 with the medium 16, such as where the launch is carried out by placing the apparatus in direct contact with the sample medium, thereby bringing the radiation source into close proximity with the sample to be analyzed. After _1g_ WO 97!28438 PCT/LTS97/01370 the launch, the reflected radiation is collected using optically active means, such as light converging means or beam deflection optics. Alternatively, the sample ' interface optic means 14 can comprise fiber optic waveguides coupled to the apparatus in order to enable remote apparatus placement and operation. Other configurations are provided wherein a single fiber optic bundle is employed to transmit the radiation to and from the medium. An optrode disposed at the end of the single bundle transmits the near-IR radiation to the sample medium 16 and receives spectrally modified radiation therefrom which is directed back through the bundle to the apparatus 1o. Sapphire or high-grade quartz can be used as optical elements in the above fiber optic waveguides, as those materials have very good transmission characteristics in the near-IR spectral range.
The reflected light in the first light path is communicated with a first filter means 22 which 20 has been configured to pass specific wavelengths of light which are independent of any analyte concentration. In one configuration, the first filter means can comprise a narrow band-pass filter which has near-IR absorption characteristics that selectively pass a region of radiation containing wavelengths with substantially no correlation with the concentration of the analyte. Radiation emerging from the first filter means 22 is then communicated to a first detection means 24. Communication of the radiation to the first 3fl detection means can be carried out via a focusing means 26, e.g., a collimating lens or the like.
Alternatively, the apparatus 10 can include a radiation detector that is capable of directly receiving radiation from the first filter means.
The first detection means detects and converts the passed radiation into a signal that is representative of the intensity of the analyte-independent radiation. In one particular apparatus, the first detection means 24 comprises a lead sulfide photodetector that is able to scan the range of wavelengths from about 1100 to at least about 3500 nm ' in steps of 1 nm.
Signals obtained from the first detection means can be readily converted into digital signals, e.g, digital signals indicative of the intensity of the analyte-independent wavelengths, using an analog/digital converter. The digitized information is readily available for input into a microprocessor or other electronic memory means, such as those known in the art.
Referring still to Figure 1, the reflected light in the second light path 22 is passed to an adjustable filter means 28 which is capable of having its absorption characteristics adjusted in response to a signal that is either externally generated, or that has been generated by the apparatus 10. The adjustable filter means generally comprises a screen filter, such as a neutral density filter, having absorption characteristics that are adjusted to variably attenuate the intensity of radiation as dictated by an external signal or system command. The degree of attenuation provided by the adjustable filter means 28 is based upon a predetermined factor selected to ensure that radiation emitted from the adjustable filter will be at a constant value regardless of the intensity of the pre-filtered radiation. In one particular apparatus, the attenuation provided by the adjustable filter means is regulated by a feedback signal generated by the first detection means 24.
Attenuated radiation emerging from the adjustable filter means 28 is communicated to a principal analyte filter 30 which has optical characteristics capable of selectively passing one or more wavelengths from each of the distinct nonoverlapping regions of wavelengths launched by the radiation source 12. The wavelengths passed by the ' principal analyte filter are selected to have a correlation with the concentration of the analyte.
A second filter means 32 is arranged in the apparatus 10 relative to the principal analyte filter 30 such that selectively~passed wavelengths emerging from the principal analyte filter interact with the second filter means, whereby the intensity of each passed wavelength is independently attenuated by the second filter means. The attenuations provided by the second filter means can be determined, for example, by an independent set of weighting factors derived using chemometrics techniques.
In one particular configuration, the weighting factors are determined using a partial least squares or principal component regression of an original spectrum obtained from a sample containing the analyte. The second filter means 32 can be constructed using a suitable substrate layer that is capable of transmitting radiation at least in the 600 to 3500 nm range. The substrate layer is generally coated with one or more layers of metals and/or oxides that are conventional in the art to provide a plurality of attenuating filter densities. Such coatings can be applied to the substrate using emulsion or chemical vapor deposition (CVD) techniques well known in the art. In an alternative apparatus, the second filter means is a photographic mask having spectral lines of optical density that are proportional to weighting functions determined using a rotated principal components or least squares analysis technique.
After attenuation by the second filter means, the independent wavelengths are communicated with a second detection means 34, such as a PbS
WO 97/28438 PCT/US97l01370 detector or the like. As described above, the wavelengths emerging from the second filter means can be communicated to the second detection means via a focusing means 36, e.g., a collimating lens or the ' like. Alternatively, the apparatus 10 can include a radiation detector capable of directly receiving radiation from the second filter means.
The second detection means detects and converts the attenuated wavelengths emitted from the second filter means into a signal which can then be applied toward an analyte specific algorithm to determine analyte concentration. Specifically, signals obtained from the second detection means can be readily converted into digital signals using an analog/digital converter. The digitized information is readily available for input into a microprocessor where it is used to provide an analyte concentration which can be visualized on a display device and/or recorded on an output recorder.
The apparatus 10 can be used to obtain measurements of analyte concentration in a variety of complex media, such as in aqueous media having complex spectral backgrounds. In one application, the apparatus can be used in the determination of blood analyte concentrations, particularly organic blood analytes such as, but not limited to, glucose, urea (BUN), lipids, bilirubin and alcohol. The blood analyte can be present in an in vitro sample medium (e. g., a blood sample), or the apparatus can be used to measure blood analytes in tissue. However, the apparatus 10 is particularly adapted for use in field applications, e.g., in the measurement of blood alcohol, or in home health monitoring, e.g., in blood glucose determination.
Referring now to Figure 2, an alternative apparatus for measurement of analyte concentration in a complex aqueous medium is generally indicated at 60.
The apparatus includes a radiation source 62 which provides a plurality of distinct, nonoverlapping regions of wavelengths in the approximate range of 600 ' to 3500 nm. Radiation from source 62 is transmitted to an optically active means 64 for receiving and directing the radiation into a beam path and/or for passing selected wavelengths, such as a collimating lens, selective filtering means or the like.
Near-IR radiation emerging from means 64 is communicated through a beam splitter 66, whereby the radiation is divided into two beams, respectively indicated at 68 and 70. The first beam 68 from beam splitter 66 is transmitted to a sample medium 72 containing an unknown concentration of an analyte of interest. In Figure 2, the sample medium 72 comprises a sample cell formed from a suitable substrate capable of transmitting radiation in the near-IR range of interest. In one case, the sample can comprise a blood serum sample, wherein it is desired to determine the concentration of blood analytes. Alternatively, the first beam 68 can be transmitted to a sample surface such as a tissue surface using direct interfacing means or indirect interfacing means, e.g., fiber optic waveguides means such as those described supra. In this manner, the concentration of blood analytes present in the tissue sample can be non-invasively determined using reflective near-IR
measurement of the absorption spectrum of radiation which has interacted with the tissue sample.
Radiation, including the spectrally modified radiation that has interacted with the constituents of the sample, e.g., the analyte of interest, is then collected and directed to an optical transfer cell 74 which is disposed in the beam path. The optical transfer cell 74 comprises a positive correlation filter system having an absorption spectrum sufficient to accept the radiation and selectively emphasize one or more wavelengths therefrom having high correlation with the concentration of an analyte of interest, and substantially no correlation with interfering components present in the sample. The positive ' correlation filter system thus passes a population of selected wavelength ranges which provide analyte-specific information, as well as information about the measurement background and information that can be used to correct for instrument changes or interference effects. Radiation emerging from the optical transfer cell 74 is received by a detection means 76 for converting the spectrally modified radiation into a signal that is representative of the intensity of that radiation. The detection means can comprise a broad spectrum photodetector such as an PbS photodetector or the like.
Referring still to Figure 2, the second beam 70 from beam splitter 66 is transmitted to an optically active element 78 which is disposed in the beam path. In one configuration, the optically active element 78 comprises a neutral density filter means having absorption characteristics sufficient to attenuate radiation equally over a selected range of near-IR wavelengths. In an alternative configuration, the optically active element 78 is an optical transfer cell that includes a positive correlation filter system having an absorption spectrum that is identical to the absorption spectrum of optical transfer cell element 74. The radiation emerging from the optically active element 78 is received by a detection means 80 for converting the radiation into signals representative of the intensity thereof.
The positive correlation filter systems can be farmed from a single substrate layer having an optically active coating which imparts absorption characteristics capable of selectively emphasizing one ar more wavelengths having high correlation with a WO 97!28438 PCT/IFS97/01370 particular analyte concentration. In particular system configurations, the positive correlation filter comprises a plurality of filter layers, each layer ' having a selected filter density and/or filter thickness suitable to provide a desired absorption characteristic. In one case, at least one layer of the system has a filter density and/or thickness that comprises a wavelength weighting factor means, wherein the weighting factor provides enhanced positive correlation of a passed wavelength with the concentration of an analyte in the selected sample medium.
The signals generated by detection means 76 and 80 are then communicated to a means 82 for converting those signals into a digital signal indicative of the ratio of the intensity of the radiation emerging from the source 62 and the corresponding spectrally modified radiation emerging from the sample. In this manner, changes in the intensity of the radiation emerging from the source 62 can be corrected for, eliminating a potential source of error in the measurement obtained from the system.
Further, the ratio of the signals can then be converted to digital form and interpreted to determine analyte concentration using an internal microprocessor 84 system or an associated system using methods known in the art.
If desired, the microprocessor can be programmed to calculate analyte concentration by application of a chemometrics algorithm to the ratio signal. The appropriate algorithm can be determined using the above-described chemometrics techniques, such as a least squares analysis or rotated principal component analysis of an original absorption spectrum of the analyte of interest.
It is to be understood that white the invention has been described in conjunction with preferred specific embodiments thereof, the foregoing description, as well as the examples which follow, are intended to illustrate and not limit the scope of the invention, other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.
Example A noninvasive glucose measurement was obtained using the method of the invention. Particularly, reflE:ctive oK>tical measurements in the near-IR
region of approximately 1100 nm to 3500 nm were carried out. Spectral scans were collected from volunteer forearm subjects, ~.asing an instrument having a Tungsten-Mercury (W-Hg) radiation source, a Lead Sulfide (PbS) detector and a scan speed of 0.4 nm/second.
A number of specific spectral ranges were identified as containing information which can be usec:l to determine glucose concentration from a forearm tissue scan. The specified regions were determined from an in vivo glucose tolerance study conducted in tandem with invasively-obtained in vitro blood glucose concentration determinations. In particular, time dependent scans taken during the in vivo tolerance study are depicted in Figure 3. As can be seen, significant changes in the reflective intensity differences over the range of about 2120 to 2180 nm were recorded during the 2,0 time course of the study. These changes increased in direct relation to increases in blood glucose level during the tolerance test, signifying that the range of 2120 to 2180 nm contains glucose-specific spectral information.
WO 97!28438 PCT/US97/OI370 Once the specific spectral ranges were identified, noninvasive glucose measurements were obtained using information from the four distinct ' spectral ranges. The first spectral range included radiation occurring at about 1320 to 1340 nm. This range provides a very highly ref lected signal, and there is no major glucose absorption band in this range. Information obtained from the first spectral range can be used to normalize each individual scan in order to correct for fluctuations in the radiation source, and changes due to mechanical perturbations.
The second spectral range included radiation occurring at either about 1440 to 1460 nm, or about 1940 to 1960 nm. These ranges provide a substantially non-reflected signal due to the highly absorptive water bands which attenuate diffusively reflected radiation. Information obtained from these ranges can be used for background and base line subtraction from otner measurements. These measurements allow for a pedestal adjustment to account for fluctuations induced by specular reflection signal values, and can be used to detect improper measurements.
The third range included radiation occurring at about 1670 to 2690 nm. This range provides analyte-specific information due to the presence of glucose vibrational overtone bands.
The fourth range included radiation occurring at about 2120 to 2280 nm. This range provides analyte-specific information due to glucose combination vibrational bands.
Signals obtained from the first range were used to normalize signals of other regions. This process, when repeated with each spectral scan, eliminates the problem associated with light source changes and serves to provide an internal reference.
Measurement variations induced by differences in optical interface, e.g., patient placements, were accordingly substantially reduced.
Background information was eliminated by subtracting the signals obtained in the second range, ' from the signals obtained in the third and fourth analyte-specific ranges. In this manner, the pedestal ' effect created by specular reflection, which varies with skin texture and age, was corrected for.
The normalized and base line corrected signals from the third and fourth ranges were applied in an analytical chemometric analysis. Figure 4 depicts the normalized differences between signals in the second and third ranges.
As can be seen by the results depicted in ~.5 Figure 4, increase in blood glucose level results in an increase in the signal differences between the two ranges.
The spectrally modified radiation is then split, ' wherein one portion is directed through a negative correlation cell and another through a reference cell.
Intensity of the radiation passing through the cells are compared to determine analyte concentration in the sample.
U.S. Patent No. 4,306,152 to Ross et al.
describes an optical fluid analyzer designed to minimize the effect of background absorption (i.e., the overall or base level optical absorption of the fluid sample) on the accuracy of measurement in a turbid sample or in a liquid sample which is otherwise difficult to analyze. The apparatus measures an optical signal at the characteristic optical absorption of a sample component of interest and another signal at a wavelength selected to approximate background absorption, and then subtracts to reduce the background component of the analyte-dependent signal.
The accuracy of information obtained using the above-described methods and devices is limited by the spectral interference caused by background, i.e., non-analyte, sample constituents that also have absorption spectra in the near-IR range. Appreciable levels of background noise represent an inherent system limitation, particularly when very little analyte is present. In light of this limitation, attempts have been made to improve signal-to-noise ratios, e.g., by avoiding water absorption peaks to enable the use of increased radiation intensity, by ' reducing the amount of spectral-information to be analyzed, or by using subtraction or compensation techniques based on an approximation of background absorption. Although such techniques have provided some improvement, there remains a need to provide a _5_ method and apparatus capable of rendering a more precise determination of the concentration of analytes in a liquid matrix, particularly in the context of blood glucose monitoring. ' Disclosure of the Invention Accordingly, it is a primary object of the invention to address the above-described needs in the art, by providing a method of determining the concentration of an analyte present in a sample having a varying background matrix and possibly having substantial component interferences as well. The method accounts for the similarity of structures among various components present in the sample, the I5 relative magnitude of the analyte concentration and spectral interferences provided by various sample components and instrumentation variances.
The method generally involves: (2) identifying several distinct, nonoverlapping regions of wavelengths in the near-IR range, which have high correlation to the concentration of the analyte; (2) irradiating a sample with incident radiation containing those regions in order to obtain radiation that has been spectrally attenuated as a result of interaction with sample constituents; (3) detecting the spectrally attenuated radiation; (4) measuring the intensity of the spectrally attenuated radiation at a wavelength in nonoverlapping regions of wavelengths;
and (5) correlating the measurements to obtain a value indicative of the concentration of the analyte.
It is also an object of the invention to provide a spectrophotometric apparatus for determining the concentration of an analyte present in a sample having a varying background matrix and substantial component interferences. The apparatus is used in a multi-spectral analysis to obtain spectral information containing analyte-specific signals as well as signals _7_ related to instrument background noise and interfering spectral information.
Chemometrics techniques are used to configure filter elements capable of enhancing the correlation of analyte-specific information with the concentration of the analyte and to derive system algorithms capably: of determining analyte concentration values.
In one aspect of the invention, an apparatus is provided which includes a specialized optic;al transfer cell that is capable of enhancing the correlation of analyte-specific information with the concentration of the analyte. The specialized optical transfer cell contains a positive correlation filter adapted to selectively emphasize wavelengths having high correlation witri the concentration of a selected analyte. The emphasized wavelengths are communicated to a means for receiving the information and converting the same into a signal representative of the intensity of the wavelength.
According to a first aspect of the invention, there is provided an apparatus for determining the concentration of an analyte in a sample, comprising: (a) means for-irradiating the sample with incident radiation containing a plurality of distinct, 1'~ nonoverlapping spectral regions of wavelengths in the near-infrared spectrum; (b) means for collecting reflected radiation emergin~~ from the sample and directing said reflected radiation into first And second light paths, wherein the first light path comprises radiation from a first spectral region of wavelengths; (c) first filter means disposed in the first light path, wherein the first filter means is capable of selectively passing radiation having substantially no correlation with the concentration of the analyte; (d) first detection means for receiving selectively passed radiation emerging from the first filter means and for converting the same into a signal representative of the intensity of said radiation; (e) adjustable filter rneans disposed in the second light path, wherein the adjustable filter means attenuates the intensitar of radiation in the second light path; (f) principal analyte 2'_i filter means capable of receiving attenuai.ed radiation emerging from the adjustable filter means, and selectively passing one or more independent wavelengths therefrom, wherein the one or more indepf:ndent wavelengths are specifically correlated with the concentration of the analyte; (g;9 second filter means capable of receiving the one or more independent wavelengths emerging from the principal analyte filter means and 3() attenuating the intensity of each indepE:ndent wavelength; and (h) second detection means for receiving the attenuated independent wavelengths emerging from the second filter means and converting thf~~ detected wavelengths into a signal representative of the intensity of said wavelengths.
-7a-According to a second aspect of the invention, there is provided an apparatus for determining the concentration of an analyte in a sample, comprising: (a) a source capable of emitting radhation containing a plurality of distinct, nonoverlapping spectral regions in the near-infrared spectrum; (b) means for dividing radiation emitted by s the source of part (a) into first and second beam paths; (c) means for irradiating the sample with the radiation in the first beam path, thereby providing reflected radiation; (d) means for collecting the reflected radiation emerging from the sample and directing said reflected radiation into a reflected light path; (e) a first optical transfer cell disposed in the reflected light path, said first cell comprising first positive correlation filter means having absorption characteristics adapted to accept the reflected radiation and emphasize one or more wavelengths from the reflected r<3diation, wherein said one or more wavelengths have high correlation with the concentration of the analyte in the sample; (f) means for receiving the one or more emphasized wavelengths from the first optical transfer cell and for converting the same into aignals representative of the intensity of said emphasized 1:i wavelengths; (g) a second opkic~al transfE~r cell disposed in the second beam path, said second cell comprising neutral density filter means having absorption characteristics sufficient to attenuate the intensity of thE: radiation from the second beam path equally over a selected range of near-infrared wavelengths; (h) means for receiving attenuated radiation from the second optical transfer cell and for converting the same into signals representative of the intensity thereof; and (i) means for calculating the concentration of the analyte in the sample using the signals generated by means (f) and (h) .
According to a third aspect of the invention, there is provided an apparatus for determining the concentration of an analyte in a sample, comprising: (a) a source capable of emitting radiation containing a plurality of distinct, nonoverlapping 2.'i spectral regions of wavelength in the rear-infrared spectrum; (b) means for dividing radiation emitted by the source into first and second beam paths; (c) means for irradiating the sample with the radiation in the first beam path, thereby providing reflected radiation; (d) means for collecting the reflected radiation emerging from the sample and directing said reflected radiation into a reflected light path; (e) a first optical transfer cell disposed in the reflected light path, said first call comprising first positive correlation filter means having ak>sorption characteristics adapted to accept the reflected radiation and emphasize one or more wavelengths from the reflected radiation, wherein said one or more wavelengths have high correlation with the concentration of the analyte in the sample; (f) means for receiving the one or more emphasized wavelengths from the first -7b-optical transfer cell and for converting the same into signals representative of the intensity of said emphasized wavelengths; (g) a second optical transfer cell disposed in the second beam path, said second cell comprising a second positive correlation filter means having absorption characteristics identical to those of the first positive correlation filter means; (h) rneans for receiving attenuated radiation from the second optical transfer cell and for converting the same into signals representative of the intensity thereof; and (i) means for calculating the concentration of the analyte in the sample using the signals generated by means (f) and (h).
Brief Description of the Fictures Figure 1 is a diagramrraatic representation of an apparatus constructed according to the invention.
Figure 2 is a diagrammatiic representation of a correlation spectrometer apparatus constructed according to the invention.
Figure 3 is a graph illustrating time dependent scans taken during an In vivo glucose tolerance study.
Figure 4 depicts in graph form the results obtained from a noninvasive determination of blood glucras~e concentration conducted using the method of the invention.
Modes for Carrvina Out the Invention Before the invention is described in detail, it is to be understood that this invention is not WO 97/28438 fCT/US97/01370 limited to the particular component parts of the devices or methods described, as such may vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an analyte'° includes mixtures of analytes, reference to "an optical transfer cell"
includes two or more optical transfer cells, "a means for ref lectively transmitting radiation" includes two or more such means, "a wavelength" includes two or more wavelengths, "a chemometrics algorithm" includes two or more algorithms, and the like.
In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings:
"Chemometrics" relates to the application of mathematical, statistical and pattern recognition techniques in chemical analysis applications. See, e.g., Brown et al. (1990) Anal. Chem. 62:84-101.
Chemometrics is practiced herein in the context of developing and using noninvasive diagnostic instrumentation that employs advanced signal processing and calibration techniques. Signal processing is used to improve the accessibility of physically significant information in analytical signals. Examples of signal processing techniques include Fourier transformation, first and second derivatives, and digital or adaptive filtering. ' In the context of chemometrics, "calibration" refers to the process of relating data ' measurements to a chemical concentration for the purpose of quantification. Particularly, statistical _g_ WO 97128438 PCTl1JS97/01370 calibrations using chemometric methods can be used to extract specific information from a complex set of data. Such methods of calibration include linear ' regression, multiple-linear regression, partial linear regression, and principal components analysis. In other applications, calibrations can be carried out using artificial neural networks, genetic algorithms and rotated principal components analysis.
Instrumentation that detects information for one or more constituents in a complex chemical matrix must rely upon analysis algorithms (such as those derived using chemometrics) in order to reveal information that is specific for one or more chemical constituent. Chemometrics techniques can be used to compare unknowns with calibrated standards and data bases to provide advanced forms of cluster analysis, and to extract features from an unknown sample that can be used as information in statistical and mathematical models.
"Principal components analysis" (PCA) is one method of data reduction which can be performed in the application of chemometric techniques to spectroscopic measurement of chemical analytes in a complex matrix.
PCA is used to reduce the dimensionality of a large number of interrelated variables while retaining the information that distinguishes one component from another. This reduction is effected using an eigenvector transformation of an original set of interrelated variables (e. g., an absorption spectrum}
into a substantially smaller set of uncorrelated principal component (PC) variables that represents most of the information in the original set. The new set of variables is ordered such that the first few retain most of the variation present in all of the original variables. See, e.g., Jolliffe, L.T., Principal Component Analysis, Sprinter-Verlag, New York (1986). More particularly, each PC is a linear WO 97/28438 PCTlUS97/01370 combination of all the original measurement variables.
The first is a vector in the direction of the greatest variance of the observed variables. The succeeding PCs are chosen to represent the greatest variation of ' the measurement data and to be orthogonal to the previously calculated PC. Therefore, the PCs are ' arranged in descending order of importance.
The term ''weighting constant" includes the wavelength coefficients of partial least squares regression and/or principal components regression, or any constant obtained from any statistical calibration that can be used to calculate values (such as analyte concentration) for unknown samples. A "wavelength weighting factor" is an embodiment of a weighting constant which is used in the construction of an optical filter means capable of emphasizing wavelength-specific information from spectral data.
The wavelength-specific information can be used to determine desired values relating to the sample undergoing analysis (e.g., analyte concentration). A
wavelength weighting factor can be embodied as a particular filter density (e.g., neutral or wavelength-specific), filter thickness, or the like, such parameters having been determined using the above-described statistical calibration techniques.
The term "optical transfer cell" encompasses any optically active element that partially absorbs incident radiation in the visible, ultraviolet, or infrared spectral regions, wherein the partial absorption is selective with respect to wavelength.
For the purposes of the present invention, an optical transfer cell generally comprises an optical filter means having absorption characteristics that were derived from a partial least squares or principal components regression analysis. The optical filter means is used to selectively emphasize wavelengths having high correlation with a selected analyte concentration. "High correlation," or "close correlation" refers to the quantitative association between the absorption spectrum at a particular wavelength and a particular analyte concentration, wherein the two variables have a correlation coefficient (r) of 0.9 or higher.
A "positive correlation filter" is an optical filter means having an absorption spectrum sufficient to emphasize radiation of particular wavelengths corresponding to the target analyte and not to other absorbing analytes. Thus, the positive correlation filter provides an optimal transfer function that is highly correlated with the analyte concentration in the sample being measured. An ideal positive correlation filter would correlate perfectly with a target analyte (i.e., the correlation coefficient r would be +1.0), and not correlate at all with all other interfering absorbing analytes in a particular sample (r would be 0.0). The synthesis of positive correlation filters is carried out herein using chemometric techniques to determine appropriate wavelength weighting factors.
A "neutral density filter" refers to a standard optical filter means having a flat absorption spectrum. A neutral density filter can be used in concert with correlation filters in a filter system to provide a weighting factor to attenuate absorbances due to the analyte at selected wavelengths and further improve the accuracy of the correlation provided by the system. A neutral density filter can have an absorption spectrum sufficient to attenuate radiation equally at all wavelengths in the range of interest.
- As used herein, an "aqueous medium'r encompasses any substrate relating to, made from, or comprising water. Thus, an aqueous medium includes media wherein water is the major component, i.e., is present in an amount of at least about 50%, as well as WO 97128438 PCT/US9?/01370 wherein water is a solvent but is present in amounts of less than about 50%. Aqueous mediums are specifically defined herein to include mammalian tissue. ' The term "blood analyte" refers to a blood constituent that is absorbing in the near-IR range, "
the measurement of which is useful in patient monitoring or in the provision of health care.
As used herein, the term "near infrared°' or "near-IR" encompasses radiation in a spectrum ranging from approximately 660 nm to 3500 nm, but typically in the range of approximately 1050 to 2850 nm, and mare typically in the range of approximately 1100 to about 2500 nm.
The term "background absorption" relates to the overall or base level of optical absorption of an aqueous sample which is to be analyzed, from which the absorption of a selected constituent departs at one or more characteristic wavelengths to an extent indicative of the concentration of the selected constituent. When the level of background absorption is high in relation to the characteristic absorption of the selected constituent, such as in complex aqueous media where numerous interfering constituents are found, accurate measurement of the magnitude of a slight change in the absorption at the characteristic wavelength of a constituent of interest requires application of the chemometrics techniques described herein. This is particularly so in applications wherein the overall concentration of the constituent of interest is low relative to the aqueous medium, e.g., in the measurement of blood analytes.
General Methods A spectrophotometric method is provided for determining the concentration of an analyte in a liquid sample using near-IR radiation. In contrast to WO 97/28438 PCT/US97/013'70 prior techniques, the present method uses all of the spectral information contained in the near-IR region in order to obtain a set of measurements that can be used to determine an analyte concentration with a heightened degree of accuracy.
The method includes the steps of (1) selecting several distinct, nonoverlapping regions of wavelengths in the near-IR, wherein each region defines a spectral range, (2) irradiating a sample using near-IR light containing the selected spectral ranges to obtain spectrally modified radiation which has been attenuated, (3) collecting and measuring the intensity of the spectrally-attenuated radiation at one or more wavelengths contained within each of the selected spectral ranges, and (4) correlating those measurements to obtain a value indicative of analyte concentration.
Spectral information obtained using this method can be subjected to a combination of mathematical transformations to arrive at a precise analyte concentration value. For example, standard statistical techniques, such as partial least squares (PLS} analysis, or principal components regression (PCR) analysis, can be used to correlate the absorbance of radiation at specific wavelengths to analyte structure and concentration. PLS techniques are described, for example, in Geladi et al. (1986) Analytica Chimica Acta 185:1-17. For a description of PCR techniques, reference may be had to Jolliffe, L.T., Principal Component Analysis, Sprinter-Verlag, New York (2986).
Accordingly, in determining blood analyte - concentration from a body tissue sample, one method involves the selection of three nonoveriapping regions of wavelengths from the near IR range spanning 1100 to 3500 nm; specifically, a first regi-on spanning 1100 to 1350 nm, a second region spanning 1430 to 1450 nm or 1930 to 1950 nm, and a third region spanning 2000 to 2500 nm, wherein each region defines a "spectral range." The first region contains wavelengths in which proteins and other cellular components exhibit dominant spectral activity, the second region is dominated by the absorption spectrum of water, and the third region contains wavelengths in which organic analyte molecules exhibit significant spectral activity. These constituents also contribute to the absorption spectra in those regions where they are not the dominant species. Accordingly, the spectrally attenuated radiation obtained from each region contains a large amount of interrelated information that must be reduced using statistical methods to obtain analyte-specific information.
The invention also involves the use of signal processing to improve the accessibility of physically significant information in the analytical signals. The intensity values of signals obtained at particular wavelengths can thus be processed to reduce the effect of instrumentation noise. The processed signals are then subjected to multivariate analysis using known statistical techniques.
The PCA method of data reduction is one preferred method used in the practice of the invention to reduce the dimensionality of a large number of interrelated variables while retaining information that distinguishes one component from another. Data reduction is carried out using an eigenvector transformation of an original set of interrelated variables (e.g., the absorption spectrum) into a substantially smaller set of uncorrelated principal component (PC) variables that represents most of the information in the original set. The new set of variables is ordered such that the first few retain most of the variation present in the original set.
WO 97!28438 PCT/US97/01370 The principal component vectors can be transformed by orthogonal rotation against an average value for the absorbance to obtain both a known ' wavelength and the relative value of the absorbance at that wavelength which is attributable to the analyte.
' By performing this analysis on information obtained from each of the three spectral regions, cross-correiating the principal component vectors via a linear algorithm, and using subtractive methods to remove the effect of interfering analytes, values are obtained which can be used in a system algorithm to determine the concentration of the analyte.
Multivariate techniques are used to provide a model that relates the intensity of radiation at specific wavelengths in each spectral region to analyte concentrations in a particular sample matrix, e.g., body tissue. The model is constructed using two sets of exemplary measurements that are obtained simultaneously, the first set of measurements, the "prediction set," comprising spectral data, e.g., radiation intensity at selected wavelengths, and the second set of measurements, the "calibration set,"
comprising highly accurate analyte concentrations that have been determined using invasive sampling techniques. The procedure is carried out over a range of anaiyte concentrations to provide calibration and prediction data sets.
Measurements obtained in both the calibration set and the prediction set are subjected to multivariate analysis, such as by the use of commercially available multivariate model developing software programs, to provide an initial model. The initial model is applied to the prediction data to derive analyte concentration values that can be compared to the values obtained by the invasive techniques. By iteratively performing the above steps, a refined model is developed which can be used WO 97!28438 PCT/I1S97101370 to establish a system algorithm for use in analyzing data obtained by the methods of the invention.
The above-described multivariate techniques can also be used to design an optically active element "
capable of enhancing correlation of spectral information with analyte concentration, e.g., a positive correlation filter system. Particularly, the solutions obtained using multivariate analysis can be used to determine optical parameters, such as absorption characteristics, for positive correlation filter systems.
In the practice of the invention, non-analyte specific information from the various nonoverlapping spectral regions is also used, for example, to normalize each spectral scan, to subtract background and base line interferences, or to provide signal values used to detect an inaccurate measurement.
When determining a blood analyte concentration in a body tissue sample, measurements taken in the spectral range spanning approximately 1320 - 1340 nm provide a highly reflected, unattenuated, signal, as there are no major absorption bands present in the region. By collecting and measuring the intensity of radiation in that range, a value is obtained which can be used to estimate the actual intensity of the near-IR light used to irradiate the sample. The value can be used to normalize each individual scan and to correct for fluctuations in the intensity of the light source which could effect the accuracy of analyte concentration values obtained using the method of the invention.
Additionally, measurements taken in the spectral ranges spanning approximately 1430 - 1450 nm and approximately 1930 - 1950 nm provide substantially non-reflected, highly attenuated, signals, as a result WO 97!28438 PCT/US9710I370 of the two dominant absorption peaks occurring at about 1440 and 1935 nm in the near-IR absorption spectrum for water. By collecting and measuring the intensity of radiation in one or both of those ranges, a value is obtained which can be used to estimate the intensity of near-IR light that is not totally absorbed by the irradiated sample. The value can be used to subtract background or base-line information from the analyte-specific signals obtained in other regions and/or to provide an internal reference to detect inaccurate measurements. The value can be subtracted from each spectral measurement obtained using the present method in order to correct for the pedestal effect caused by specular reflection which varies with skin texture and age.
Measurements of substantially unattenuated signals obtained from a first region (e.g., the spectral range spanning approximately 1320 - 1340 nm) and measurements of highly attenuated signals obtained from a second region (e. g., the spectral ranges spanning approximately 1430 - 1450 nm and approximately 1930 - 1950 nm) can also be used to compare diffusely reflected radiation with specular radiation. If the signals in the two regions have relatively comparable values, it is likely that most of the radiation used to irradiate the tissue sample was reflected from the skin surface, and thus failed to penetrate the skin to interact with the blood anaiytes. This information can be used to identify ineffective measurements arising from a failure to obtain a proper instrumentation scan of the tissue sample.
The method of the invention can be carried out using a number of spectrophotometer configurations. Referring now to Figure 1, one particular apparatus for determining the concentration of an analyte in a liquid sample is generally WQ 97!28438 PCT/US97/01370 indicated at 10. The apparatus includes a radiation source 12 which provides a plurality of distinct, nonoverlapping regions of wavelengths in the approximate range of 600 to approximately 3500 nm. A ' number of suitable radiation sources are known in the art, such as incandescent light sources directed "
across interference filters, halogen light sources, modulated by an associated chopper wheel, laser light sources, laser diode arrays, or high speed light-20 emitting diode (LED) arrays. In one particular apparatus, the radiation source 12 provides radiation at three distinct regions of wavelengths, specifically a first region of wavelengths in the near-IR, typically in the range of approximately 1100 to 1350 nm, a second region generally in the range of approximately 1930 to 1950 nm, and a third region typically in the range of approximately 2000 to 3500 nm.
The apparatus 10 also includes sample 2o interface optic means 14 which launches incident radiation from the radiation source into contact with a sample medium 16 containing an analyte. After contacting the sample medium, spectrally modified radiation emerging from the sample as diffusively reflected light is collected and delivered to a first lens system i8, whereby the light is directed into first and second light paths, respectively indicated at 20 and 22. The first lens system 18 can comprise a partial reflected mirror configuration such as those known in the art.
In various configurations, the sample interface optic means 14 can be designed to enable the close interface of the apparatus l0 with the medium 16, such as where the launch is carried out by placing the apparatus in direct contact with the sample medium, thereby bringing the radiation source into close proximity with the sample to be analyzed. After _1g_ WO 97!28438 PCT/LTS97/01370 the launch, the reflected radiation is collected using optically active means, such as light converging means or beam deflection optics. Alternatively, the sample ' interface optic means 14 can comprise fiber optic waveguides coupled to the apparatus in order to enable remote apparatus placement and operation. Other configurations are provided wherein a single fiber optic bundle is employed to transmit the radiation to and from the medium. An optrode disposed at the end of the single bundle transmits the near-IR radiation to the sample medium 16 and receives spectrally modified radiation therefrom which is directed back through the bundle to the apparatus 1o. Sapphire or high-grade quartz can be used as optical elements in the above fiber optic waveguides, as those materials have very good transmission characteristics in the near-IR spectral range.
The reflected light in the first light path is communicated with a first filter means 22 which 20 has been configured to pass specific wavelengths of light which are independent of any analyte concentration. In one configuration, the first filter means can comprise a narrow band-pass filter which has near-IR absorption characteristics that selectively pass a region of radiation containing wavelengths with substantially no correlation with the concentration of the analyte. Radiation emerging from the first filter means 22 is then communicated to a first detection means 24. Communication of the radiation to the first 3fl detection means can be carried out via a focusing means 26, e.g., a collimating lens or the like.
Alternatively, the apparatus 10 can include a radiation detector that is capable of directly receiving radiation from the first filter means.
The first detection means detects and converts the passed radiation into a signal that is representative of the intensity of the analyte-independent radiation. In one particular apparatus, the first detection means 24 comprises a lead sulfide photodetector that is able to scan the range of wavelengths from about 1100 to at least about 3500 nm ' in steps of 1 nm.
Signals obtained from the first detection means can be readily converted into digital signals, e.g, digital signals indicative of the intensity of the analyte-independent wavelengths, using an analog/digital converter. The digitized information is readily available for input into a microprocessor or other electronic memory means, such as those known in the art.
Referring still to Figure 1, the reflected light in the second light path 22 is passed to an adjustable filter means 28 which is capable of having its absorption characteristics adjusted in response to a signal that is either externally generated, or that has been generated by the apparatus 10. The adjustable filter means generally comprises a screen filter, such as a neutral density filter, having absorption characteristics that are adjusted to variably attenuate the intensity of radiation as dictated by an external signal or system command. The degree of attenuation provided by the adjustable filter means 28 is based upon a predetermined factor selected to ensure that radiation emitted from the adjustable filter will be at a constant value regardless of the intensity of the pre-filtered radiation. In one particular apparatus, the attenuation provided by the adjustable filter means is regulated by a feedback signal generated by the first detection means 24.
Attenuated radiation emerging from the adjustable filter means 28 is communicated to a principal analyte filter 30 which has optical characteristics capable of selectively passing one or more wavelengths from each of the distinct nonoverlapping regions of wavelengths launched by the radiation source 12. The wavelengths passed by the ' principal analyte filter are selected to have a correlation with the concentration of the analyte.
A second filter means 32 is arranged in the apparatus 10 relative to the principal analyte filter 30 such that selectively~passed wavelengths emerging from the principal analyte filter interact with the second filter means, whereby the intensity of each passed wavelength is independently attenuated by the second filter means. The attenuations provided by the second filter means can be determined, for example, by an independent set of weighting factors derived using chemometrics techniques.
In one particular configuration, the weighting factors are determined using a partial least squares or principal component regression of an original spectrum obtained from a sample containing the analyte. The second filter means 32 can be constructed using a suitable substrate layer that is capable of transmitting radiation at least in the 600 to 3500 nm range. The substrate layer is generally coated with one or more layers of metals and/or oxides that are conventional in the art to provide a plurality of attenuating filter densities. Such coatings can be applied to the substrate using emulsion or chemical vapor deposition (CVD) techniques well known in the art. In an alternative apparatus, the second filter means is a photographic mask having spectral lines of optical density that are proportional to weighting functions determined using a rotated principal components or least squares analysis technique.
After attenuation by the second filter means, the independent wavelengths are communicated with a second detection means 34, such as a PbS
WO 97/28438 PCT/US97l01370 detector or the like. As described above, the wavelengths emerging from the second filter means can be communicated to the second detection means via a focusing means 36, e.g., a collimating lens or the ' like. Alternatively, the apparatus 10 can include a radiation detector capable of directly receiving radiation from the second filter means.
The second detection means detects and converts the attenuated wavelengths emitted from the second filter means into a signal which can then be applied toward an analyte specific algorithm to determine analyte concentration. Specifically, signals obtained from the second detection means can be readily converted into digital signals using an analog/digital converter. The digitized information is readily available for input into a microprocessor where it is used to provide an analyte concentration which can be visualized on a display device and/or recorded on an output recorder.
The apparatus 10 can be used to obtain measurements of analyte concentration in a variety of complex media, such as in aqueous media having complex spectral backgrounds. In one application, the apparatus can be used in the determination of blood analyte concentrations, particularly organic blood analytes such as, but not limited to, glucose, urea (BUN), lipids, bilirubin and alcohol. The blood analyte can be present in an in vitro sample medium (e. g., a blood sample), or the apparatus can be used to measure blood analytes in tissue. However, the apparatus 10 is particularly adapted for use in field applications, e.g., in the measurement of blood alcohol, or in home health monitoring, e.g., in blood glucose determination.
Referring now to Figure 2, an alternative apparatus for measurement of analyte concentration in a complex aqueous medium is generally indicated at 60.
The apparatus includes a radiation source 62 which provides a plurality of distinct, nonoverlapping regions of wavelengths in the approximate range of 600 ' to 3500 nm. Radiation from source 62 is transmitted to an optically active means 64 for receiving and directing the radiation into a beam path and/or for passing selected wavelengths, such as a collimating lens, selective filtering means or the like.
Near-IR radiation emerging from means 64 is communicated through a beam splitter 66, whereby the radiation is divided into two beams, respectively indicated at 68 and 70. The first beam 68 from beam splitter 66 is transmitted to a sample medium 72 containing an unknown concentration of an analyte of interest. In Figure 2, the sample medium 72 comprises a sample cell formed from a suitable substrate capable of transmitting radiation in the near-IR range of interest. In one case, the sample can comprise a blood serum sample, wherein it is desired to determine the concentration of blood analytes. Alternatively, the first beam 68 can be transmitted to a sample surface such as a tissue surface using direct interfacing means or indirect interfacing means, e.g., fiber optic waveguides means such as those described supra. In this manner, the concentration of blood analytes present in the tissue sample can be non-invasively determined using reflective near-IR
measurement of the absorption spectrum of radiation which has interacted with the tissue sample.
Radiation, including the spectrally modified radiation that has interacted with the constituents of the sample, e.g., the analyte of interest, is then collected and directed to an optical transfer cell 74 which is disposed in the beam path. The optical transfer cell 74 comprises a positive correlation filter system having an absorption spectrum sufficient to accept the radiation and selectively emphasize one or more wavelengths therefrom having high correlation with the concentration of an analyte of interest, and substantially no correlation with interfering components present in the sample. The positive ' correlation filter system thus passes a population of selected wavelength ranges which provide analyte-specific information, as well as information about the measurement background and information that can be used to correct for instrument changes or interference effects. Radiation emerging from the optical transfer cell 74 is received by a detection means 76 for converting the spectrally modified radiation into a signal that is representative of the intensity of that radiation. The detection means can comprise a broad spectrum photodetector such as an PbS photodetector or the like.
Referring still to Figure 2, the second beam 70 from beam splitter 66 is transmitted to an optically active element 78 which is disposed in the beam path. In one configuration, the optically active element 78 comprises a neutral density filter means having absorption characteristics sufficient to attenuate radiation equally over a selected range of near-IR wavelengths. In an alternative configuration, the optically active element 78 is an optical transfer cell that includes a positive correlation filter system having an absorption spectrum that is identical to the absorption spectrum of optical transfer cell element 74. The radiation emerging from the optically active element 78 is received by a detection means 80 for converting the radiation into signals representative of the intensity thereof.
The positive correlation filter systems can be farmed from a single substrate layer having an optically active coating which imparts absorption characteristics capable of selectively emphasizing one ar more wavelengths having high correlation with a WO 97!28438 PCT/IFS97/01370 particular analyte concentration. In particular system configurations, the positive correlation filter comprises a plurality of filter layers, each layer ' having a selected filter density and/or filter thickness suitable to provide a desired absorption characteristic. In one case, at least one layer of the system has a filter density and/or thickness that comprises a wavelength weighting factor means, wherein the weighting factor provides enhanced positive correlation of a passed wavelength with the concentration of an analyte in the selected sample medium.
The signals generated by detection means 76 and 80 are then communicated to a means 82 for converting those signals into a digital signal indicative of the ratio of the intensity of the radiation emerging from the source 62 and the corresponding spectrally modified radiation emerging from the sample. In this manner, changes in the intensity of the radiation emerging from the source 62 can be corrected for, eliminating a potential source of error in the measurement obtained from the system.
Further, the ratio of the signals can then be converted to digital form and interpreted to determine analyte concentration using an internal microprocessor 84 system or an associated system using methods known in the art.
If desired, the microprocessor can be programmed to calculate analyte concentration by application of a chemometrics algorithm to the ratio signal. The appropriate algorithm can be determined using the above-described chemometrics techniques, such as a least squares analysis or rotated principal component analysis of an original absorption spectrum of the analyte of interest.
It is to be understood that white the invention has been described in conjunction with preferred specific embodiments thereof, the foregoing description, as well as the examples which follow, are intended to illustrate and not limit the scope of the invention, other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.
Example A noninvasive glucose measurement was obtained using the method of the invention. Particularly, reflE:ctive oK>tical measurements in the near-IR
region of approximately 1100 nm to 3500 nm were carried out. Spectral scans were collected from volunteer forearm subjects, ~.asing an instrument having a Tungsten-Mercury (W-Hg) radiation source, a Lead Sulfide (PbS) detector and a scan speed of 0.4 nm/second.
A number of specific spectral ranges were identified as containing information which can be usec:l to determine glucose concentration from a forearm tissue scan. The specified regions were determined from an in vivo glucose tolerance study conducted in tandem with invasively-obtained in vitro blood glucose concentration determinations. In particular, time dependent scans taken during the in vivo tolerance study are depicted in Figure 3. As can be seen, significant changes in the reflective intensity differences over the range of about 2120 to 2180 nm were recorded during the 2,0 time course of the study. These changes increased in direct relation to increases in blood glucose level during the tolerance test, signifying that the range of 2120 to 2180 nm contains glucose-specific spectral information.
WO 97!28438 PCT/US97/OI370 Once the specific spectral ranges were identified, noninvasive glucose measurements were obtained using information from the four distinct ' spectral ranges. The first spectral range included radiation occurring at about 1320 to 1340 nm. This range provides a very highly ref lected signal, and there is no major glucose absorption band in this range. Information obtained from the first spectral range can be used to normalize each individual scan in order to correct for fluctuations in the radiation source, and changes due to mechanical perturbations.
The second spectral range included radiation occurring at either about 1440 to 1460 nm, or about 1940 to 1960 nm. These ranges provide a substantially non-reflected signal due to the highly absorptive water bands which attenuate diffusively reflected radiation. Information obtained from these ranges can be used for background and base line subtraction from otner measurements. These measurements allow for a pedestal adjustment to account for fluctuations induced by specular reflection signal values, and can be used to detect improper measurements.
The third range included radiation occurring at about 1670 to 2690 nm. This range provides analyte-specific information due to the presence of glucose vibrational overtone bands.
The fourth range included radiation occurring at about 2120 to 2280 nm. This range provides analyte-specific information due to glucose combination vibrational bands.
Signals obtained from the first range were used to normalize signals of other regions. This process, when repeated with each spectral scan, eliminates the problem associated with light source changes and serves to provide an internal reference.
Measurement variations induced by differences in optical interface, e.g., patient placements, were accordingly substantially reduced.
Background information was eliminated by subtracting the signals obtained in the second range, ' from the signals obtained in the third and fourth analyte-specific ranges. In this manner, the pedestal ' effect created by specular reflection, which varies with skin texture and age, was corrected for.
The normalized and base line corrected signals from the third and fourth ranges were applied in an analytical chemometric analysis. Figure 4 depicts the normalized differences between signals in the second and third ranges.
As can be seen by the results depicted in ~.5 Figure 4, increase in blood glucose level results in an increase in the signal differences between the two ranges.
Claims (21)
1. An apparatus for determining the concentration of an analyte in a sample, comprising:
(a) means for irradiating the sample with incident radiation containing a plurality of distinct, nonoverlapping spectral regions of wavelengths in the near-infrared spectrum;
(b) means for collecting reflected radiation emerging from the sample and directing said reflected radiation into first and second light paths, wherein the first light path comprises radiation from a first spectral region of wavelengths;
(c) first filter means disposed in the first light path, wherein the first filter means is capable of selectively passing radiation having substantially no correlation with the concentration of the analyte;
(d) first detection means for receiving selectively passed radiation emerging from the first filter means and for converting the same into a signal representative of the intensity of said radiation;
(e) adjustable filter means disposed in the second light path, wherein the adjustable filter means attenuates the intensity of radiation in the second light path;
(f) principal analyte filter means capable of receiving attenuated radiation emerging from the adjustable filter means, and selectively passing one or more independent wavelengths therefrom, wherein the one or more independent wavelengths are specifically correlated with the concentration of the analyte;
(g) second filter means capable of receiving the one or more independent wavelengths emerging from the principal analyte filter means and attenuating the intensity of each independent wavelength; and (h) second detection means for receiving the attenuated independent wavelengths emerging from the second filter means and converting the detected wavelengths into a signal representative of the intensity of said wavelengths.
(a) means for irradiating the sample with incident radiation containing a plurality of distinct, nonoverlapping spectral regions of wavelengths in the near-infrared spectrum;
(b) means for collecting reflected radiation emerging from the sample and directing said reflected radiation into first and second light paths, wherein the first light path comprises radiation from a first spectral region of wavelengths;
(c) first filter means disposed in the first light path, wherein the first filter means is capable of selectively passing radiation having substantially no correlation with the concentration of the analyte;
(d) first detection means for receiving selectively passed radiation emerging from the first filter means and for converting the same into a signal representative of the intensity of said radiation;
(e) adjustable filter means disposed in the second light path, wherein the adjustable filter means attenuates the intensity of radiation in the second light path;
(f) principal analyte filter means capable of receiving attenuated radiation emerging from the adjustable filter means, and selectively passing one or more independent wavelengths therefrom, wherein the one or more independent wavelengths are specifically correlated with the concentration of the analyte;
(g) second filter means capable of receiving the one or more independent wavelengths emerging from the principal analyte filter means and attenuating the intensity of each independent wavelength; and (h) second detection means for receiving the attenuated independent wavelengths emerging from the second filter means and converting the detected wavelengths into a signal representative of the intensity of said wavelengths.
2. The apparatus of claim 1, wherein the first filter means comprises a narrow band-pass filter.
3. The apparatus of claim 2, wherein the adjustable filter means comprises a neutral density filter used in concert with correlation filters in a filter system.
4. The apparatus of claim 3, wherein the signal obtained from the first detection means is used to regulate attenuation provided by the adjustable filter means.
5. The apparatus of claim 1, wherein the second filter means comprises a neutral density filter used in concert with correlation filters in a filter system.
6. The apparatus of claim 5, wherein the attenuation provided by the second filter means is established using weighting factors.
7. An apparatus for determining the concentration of an analyte in a sample, comprising:
(a) a source capable of emitting radiation containing a plurality of distinct, nonoverlapping spectral regions in the near-infrared spectrum;
(b) means for dividing radiation emitted by the source of part (a) into first and second beam paths (c) means for irradiating the sample with the radiation in the first beam path, thereby providing reflected radiation;
(d) means for collecting the reflected radiation emerging from the sample and directing said reflected radiation into a reflected light path;
(e) a first optical transfer cell disposed in the reflected light path, said first cell comprising first positive correlation filter means having absorption characteristics adapted to accept the reflected radiation and emphasize one or more wavelengths from the reflected radiation, wherein said one or more wavelengths have high correlation with the concentration of the analyte in the sample;
(f) means for receiving the one or more emphasized wavelengths from the first optical transfer cell and for converting the same into signals representative of the intensity of said emphasized wavelengths;
(g) a second optical transfer cell disposed in the second beam path, said second cell comprising neutral density filter means having absorption characteristics sufficient to attenuate the intensity of the radiation from the second beam path equally over a selected range of near-infrared wavelengths;
(h) means for receiving attenuated radiation from the second optical transfer cell and for converting the same into signals representative of the intensity thereof; and (i) means for calculating the concentration of the analyte in the sample using the signals generated by means (f) and (h).
(a) a source capable of emitting radiation containing a plurality of distinct, nonoverlapping spectral regions in the near-infrared spectrum;
(b) means for dividing radiation emitted by the source of part (a) into first and second beam paths (c) means for irradiating the sample with the radiation in the first beam path, thereby providing reflected radiation;
(d) means for collecting the reflected radiation emerging from the sample and directing said reflected radiation into a reflected light path;
(e) a first optical transfer cell disposed in the reflected light path, said first cell comprising first positive correlation filter means having absorption characteristics adapted to accept the reflected radiation and emphasize one or more wavelengths from the reflected radiation, wherein said one or more wavelengths have high correlation with the concentration of the analyte in the sample;
(f) means for receiving the one or more emphasized wavelengths from the first optical transfer cell and for converting the same into signals representative of the intensity of said emphasized wavelengths;
(g) a second optical transfer cell disposed in the second beam path, said second cell comprising neutral density filter means having absorption characteristics sufficient to attenuate the intensity of the radiation from the second beam path equally over a selected range of near-infrared wavelengths;
(h) means for receiving attenuated radiation from the second optical transfer cell and for converting the same into signals representative of the intensity thereof; and (i) means for calculating the concentration of the analyte in the sample using the signals generated by means (f) and (h).
8. The apparatus of claim 7, wherein the second optical transfer cell comprises a second positive correlation filter means having absorption characteristics identical to those of the first positive correlation filter means.
9. The apparatus of claim 7, wherein the means for calculating the concentration of the analyte in the sample converts the signals generated by means (f) and (h) into a digital signal indicative of the ratio of the intensity of the radiation emerging from the source and corresponding radiation emerging from the sample.
10. The apparatus of claim 7 wherein the means for calculating the concentration or the analyte in the sample comprises means for applying a chemometrics algorithm to the signals generated by means (f) and (h).
11. The apparatus of claim 7, wherein the first positive correlation filter means comprises a plurality of layers, each layer having selected absorption characteristics such that said filter means emphasizes a population of wavelengths having high correlation with the analyte concentration.
12. An apparatus for determining the concentration of an analyte in a sample, comprising:
(a) a source capable of emitting radiation containing a plurality of distinct, nonoverlapping spectral regions of wavelength in the near-infrared spectrum;
(b) means for dividing radiation emitted by the source into first and second beam paths;
(c) means for irradiating the sample with the radiation in the first beam path, thereby providing reflected radiation;
(d) means for collecting the reflected radiation emerging from the sample and directing said reflected radiation into a reflected light path;
(e) a first optical transfer cell disposed in the reflected light path, said first cell comprising first positive correlation filter means having absorption characteristics adapted to accept the reflected radiation and emphasize one or more wavelengths from the reflected radiation, wherein said one or more wavelengths have high correlation with the concentration of the analyte in the sample;
(f) means for receiving the one or more emphasized wavelengths from the first optical transfer cell and for converting the same into signals representative of the intensity of said emphasized wavelengths;
(g) a second optical transfer cell disposed in the second beam path, said second cell comprising a second positive correlation filter means having absorption characteristics identical to those of the first positive correlation filter means;
(h) means for receiving attenuated radiation from the second optical transfer cell and for converting the same into signals representative of the intensity thereof; and (i) means for calculating the concentration of the analyte in the sample using the signals generated by means (f) and (h).
(a) a source capable of emitting radiation containing a plurality of distinct, nonoverlapping spectral regions of wavelength in the near-infrared spectrum;
(b) means for dividing radiation emitted by the source into first and second beam paths;
(c) means for irradiating the sample with the radiation in the first beam path, thereby providing reflected radiation;
(d) means for collecting the reflected radiation emerging from the sample and directing said reflected radiation into a reflected light path;
(e) a first optical transfer cell disposed in the reflected light path, said first cell comprising first positive correlation filter means having absorption characteristics adapted to accept the reflected radiation and emphasize one or more wavelengths from the reflected radiation, wherein said one or more wavelengths have high correlation with the concentration of the analyte in the sample;
(f) means for receiving the one or more emphasized wavelengths from the first optical transfer cell and for converting the same into signals representative of the intensity of said emphasized wavelengths;
(g) a second optical transfer cell disposed in the second beam path, said second cell comprising a second positive correlation filter means having absorption characteristics identical to those of the first positive correlation filter means;
(h) means for receiving attenuated radiation from the second optical transfer cell and for converting the same into signals representative of the intensity thereof; and (i) means for calculating the concentration of the analyte in the sample using the signals generated by means (f) and (h).
13. The apparatus of claim 12, wherein the first positive correlation filter means comprises a plurality of layers, each layer having selected absorption characteristics such that said filter means emphasizes a population of wavelengths having high correlation with the analyte concentration.
14. The apparatus of 13, wherein the absorption characteristics of at least one layer from the first and second positive correlation filter means are established using weighting factors.
15. The apparatus of claims 6 or 14, wherein the weighting factors are derived using chemometrics techniques.
16. The apparatus of claim 15, wherein the weighting factors are derived using rotated principal components analysis of an absorption spectrum of the analyte.
17. The apparatus of claim 1, wherein the wavelengths of the incident radiation are in the range of approximately 1100 to 3500 nm.
18. The apparatus of claim 7 or 12, wherein the wavelengths of the radiation emitted by the source are in the range of approximately 1100 to 3500 nm.
19. The apparatus of any one of claims 1, 7 or 12, wherein the sample comprises body tissue and the analyte comprises an organic blood analyte.
20. The apparatus of claim 19, wherein the blood analyte is selected from the group consisting of glucose, urea (BUN), lipids, bilirubin and ethyl alcohol.
21. The apparatus of claim 20, wherein the blood analyte is glucose.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/596,409 | 1996-02-02 | ||
US08/596,409 US5747806A (en) | 1996-02-02 | 1996-02-02 | Method and apparatus for multi-spectral analysis in noninvasive nir spectroscopy |
PCT/US1997/001370 WO1997028438A1 (en) | 1996-02-02 | 1997-01-31 | Method and apparatus for multi-spectral analysis in noninvasive nir spectroscopy |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2244111A1 CA2244111A1 (en) | 1997-08-07 |
CA2244111C true CA2244111C (en) | 2003-04-08 |
Family
ID=24387178
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002244111A Expired - Fee Related CA2244111C (en) | 1996-02-02 | 1997-01-31 | Method and apparatus for multi-spectral analysis in noninvasive nir spectroscopy |
Country Status (16)
Country | Link |
---|---|
US (2) | US5747806A (en) |
EP (1) | EP0877926B1 (en) |
JP (2) | JPH11506207A (en) |
KR (1) | KR19990082236A (en) |
CN (1) | CN1101934C (en) |
AT (1) | ATE239910T1 (en) |
BR (1) | BR9707246A (en) |
CA (1) | CA2244111C (en) |
CZ (1) | CZ239298A3 (en) |
DE (1) | DE69721732T2 (en) |
DK (1) | DK0877926T3 (en) |
HK (1) | HK1019635A1 (en) |
NZ (1) | NZ331158A (en) |
PL (1) | PL184609B1 (en) |
TW (1) | TW426802B (en) |
WO (1) | WO1997028438A1 (en) |
Families Citing this family (379)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6240306B1 (en) | 1995-08-09 | 2001-05-29 | Rio Grande Medical Technologies, Inc. | Method and apparatus for non-invasive blood analyte measurement with fluid compartment equilibration |
DE19601923C1 (en) * | 1996-01-12 | 1997-07-24 | Inst Chemo Biosensorik | Method and device for detecting organic substances |
US6040578A (en) * | 1996-02-02 | 2000-03-21 | Instrumentation Metrics, Inc. | Method and apparatus for multi-spectral analysis of organic blood analytes in noninvasive infrared spectroscopy |
US5747806A (en) * | 1996-02-02 | 1998-05-05 | Instrumentation Metrics, Inc | Method and apparatus for multi-spectral analysis in noninvasive nir spectroscopy |
US6544193B2 (en) * | 1996-09-04 | 2003-04-08 | Marcio Marc Abreu | Noninvasive measurement of chemical substances |
US7890158B2 (en) * | 2001-06-05 | 2011-02-15 | Lumidigm, Inc. | Apparatus and method of biometric determination using specialized optical spectroscopy systems |
US7383069B2 (en) * | 1997-08-14 | 2008-06-03 | Sensys Medical, Inc. | Method of sample control and calibration adjustment for use with a noninvasive analyzer |
US6115673A (en) * | 1997-08-14 | 2000-09-05 | Instrumentation Metrics, Inc. | Method and apparatus for generating basis sets for use in spectroscopic analysis |
US6070093A (en) | 1997-12-02 | 2000-05-30 | Abbott Laboratories | Multiplex sensor and method of use |
JP3507437B2 (en) | 1998-05-13 | 2004-03-15 | シグナス, インコーポレイテッド | Collection assembly for transdermal sampling systems |
US6097975A (en) * | 1998-05-13 | 2000-08-01 | Biosensor, Inc. | Apparatus and method for noninvasive glucose measurement |
US6501982B1 (en) * | 1999-01-22 | 2002-12-31 | Sensys Medical, Inc. | System for the noninvasive estimation of relative age |
US6587702B1 (en) * | 1999-01-22 | 2003-07-01 | Instrumentation Metrics, Inc | Classification and characterization of tissue through features related to adipose tissue |
AT406711B (en) * | 1999-02-25 | 2000-08-25 | Joanneum Research Forschungsge | PROCEDURE FOR THE SPECTROSCOPIC DETERMINATION OF THE CONCENTRATION OF ALCOHOLS WITH 1 TO 5 CARBON ATOMS |
US7123844B2 (en) * | 1999-04-06 | 2006-10-17 | Myrick Michael L | Optical computational system |
US6529276B1 (en) | 1999-04-06 | 2003-03-04 | University Of South Carolina | Optical computational system |
US6247648B1 (en) * | 1999-04-29 | 2001-06-19 | Symbol Technologies, Inc. | Bar code scanner utilizing multiple light beams output by a light beam splitter |
US6475800B1 (en) | 1999-07-22 | 2002-11-05 | Instrumentation Metrics, Inc. | Intra-serum and intra-gel for modeling human skin tissue |
JP2003508744A (en) * | 1999-08-31 | 2003-03-04 | シーエムイー テレメトリクス インコーポレーテッド | Analyte quantification method using NIR, adjacent visible spectrum and discrete NIR wavelength |
WO2001016578A1 (en) * | 1999-08-31 | 2001-03-08 | Cme Telemetrix Inc. | Method for determination of analytes using near infrared, adjacent visible spectrum and an array of longer near infrared wavelengths |
US6919566B1 (en) * | 1999-08-31 | 2005-07-19 | Nir Diagnostics Inc. | Method of calibrating a spectroscopic device |
US6816605B2 (en) | 1999-10-08 | 2004-11-09 | Lumidigm, Inc. | Methods and systems for biometric identification of individuals using linear optical spectroscopy |
US7519406B2 (en) * | 2004-04-28 | 2009-04-14 | Sensys Medical, Inc. | Noninvasive analyzer sample probe interface method and apparatus |
US20060211931A1 (en) * | 2000-05-02 | 2006-09-21 | Blank Thomas B | Noninvasive analyzer sample probe interface method and apparatus |
US7606608B2 (en) * | 2000-05-02 | 2009-10-20 | Sensys Medical, Inc. | Optical sampling interface system for in-vivo measurement of tissue |
US6442413B1 (en) | 2000-05-15 | 2002-08-27 | James H. Silver | Implantable sensor |
US7006858B2 (en) * | 2000-05-15 | 2006-02-28 | Silver James H | Implantable, retrievable sensors and immunosensors |
US7181261B2 (en) | 2000-05-15 | 2007-02-20 | Silver James H | Implantable, retrievable, thrombus minimizing sensors |
US7769420B2 (en) * | 2000-05-15 | 2010-08-03 | Silver James H | Sensors for detecting substances indicative of stroke, ischemia, or myocardial infarction |
US7079252B1 (en) | 2000-06-01 | 2006-07-18 | Lifescan, Inc. | Dual beam FTIR methods and devices for use in analyte detection in samples of low transmissivity |
EP1299709A1 (en) * | 2000-06-02 | 2003-04-09 | Hema Metrics, Inc. | System and method for measuring blood urea nitrogen, blood osmolarity, plasma free haemoglobin and tissue water content |
US6525319B2 (en) | 2000-12-15 | 2003-02-25 | Midwest Research Institute | Use of a region of the visible and near infrared spectrum to predict mechanical properties of wet wood and standing trees |
US6549861B1 (en) | 2000-08-10 | 2003-04-15 | Euro-Celtique, S.A. | Automated system and method for spectroscopic analysis |
US6633772B2 (en) | 2000-08-18 | 2003-10-14 | Cygnus, Inc. | Formulation and manipulation of databases of analyte and associated values |
CA2408338C (en) * | 2000-08-18 | 2009-09-08 | Cygnus, Inc. | Methods and devices for prediction of hypoglycemic events |
WO2002016905A2 (en) | 2000-08-21 | 2002-02-28 | Euro-Celtique, S.A. | Near infrared blood glucose monitoring system |
US20020026111A1 (en) * | 2000-08-28 | 2002-02-28 | Neil Ackerman | Methods of monitoring glucose levels in a subject and uses thereof |
US7138156B1 (en) | 2000-09-26 | 2006-11-21 | Myrick Michael L | Filter design algorithm for multi-variate optical computing |
JP4054853B2 (en) * | 2000-10-17 | 2008-03-05 | 独立行政法人農業・食品産業技術総合研究機構 | Blood analysis using near infrared spectroscopy |
US6534768B1 (en) * | 2000-10-30 | 2003-03-18 | Euro-Oeltique, S.A. | Hemispherical detector |
US6593572B2 (en) | 2000-12-13 | 2003-07-15 | Midwest Research Institute | Method of predicting mechanical properties of decayed wood |
US6406916B1 (en) | 2001-01-22 | 2002-06-18 | General Electric Company | Method and apparatus for rapid quantitation of a dihydric phenol |
US7126682B2 (en) * | 2001-04-11 | 2006-10-24 | Rio Grande Medical Technologies, Inc. | Encoded variable filter spectrometer |
US6983176B2 (en) | 2001-04-11 | 2006-01-03 | Rio Grande Medical Technologies, Inc. | Optically similar reference samples and related methods for multivariate calibration models used in optical spectroscopy |
US7043288B2 (en) | 2002-04-04 | 2006-05-09 | Inlight Solutions, Inc. | Apparatus and method for spectroscopic analysis of tissue to detect diabetes in an individual |
US8581697B2 (en) * | 2001-04-11 | 2013-11-12 | Trutouch Technologies Inc. | Apparatuses for noninvasive determination of in vivo alcohol concentration using raman spectroscopy |
US8174394B2 (en) * | 2001-04-11 | 2012-05-08 | Trutouch Technologies, Inc. | System for noninvasive determination of analytes in tissue |
US6865408B1 (en) | 2001-04-11 | 2005-03-08 | Inlight Solutions, Inc. | System for non-invasive measurement of glucose in humans |
US6862091B2 (en) | 2001-04-11 | 2005-03-01 | Inlight Solutions, Inc. | Illumination device and method for spectroscopic analysis |
US6574490B2 (en) | 2001-04-11 | 2003-06-03 | Rio Grande Medical Technologies, Inc. | System for non-invasive measurement of glucose in humans |
US6697658B2 (en) | 2001-07-02 | 2004-02-24 | Masimo Corporation | Low power pulse oximeter |
US6731961B2 (en) | 2001-11-09 | 2004-05-04 | Optiscan Biomedical Corp. | Method for transforming phase spectra to absorption spectra |
AU2002346486A1 (en) * | 2001-11-21 | 2003-06-10 | James R. Braig | Method for adjusting a blood analyte measurement |
US6862534B2 (en) * | 2001-12-14 | 2005-03-01 | Optiscan Biomedical Corporation | Method of determining an analyte concentration in a sample from an absorption spectrum |
US7355512B1 (en) | 2002-01-24 | 2008-04-08 | Masimo Corporation | Parallel alarm processor |
US8504128B2 (en) * | 2002-03-08 | 2013-08-06 | Glt Acquisition Corp. | Method and apparatus for coupling a channeled sample probe to tissue |
US8718738B2 (en) * | 2002-03-08 | 2014-05-06 | Glt Acquisition Corp. | Method and apparatus for coupling a sample probe with a sample site |
US7697966B2 (en) * | 2002-03-08 | 2010-04-13 | Sensys Medical, Inc. | Noninvasive targeting system method and apparatus |
IL163538A0 (en) * | 2002-03-08 | 2005-12-18 | Sensys Medical Inc | Compact apparatus for noninvasive measurement of glucose through nearinfrared spectroscopy |
US20050187439A1 (en) * | 2003-03-07 | 2005-08-25 | Blank Thomas B. | Sampling interface system for in-vivo estimation of tissue analyte concentration |
US20050054908A1 (en) * | 2003-03-07 | 2005-03-10 | Blank Thomas B. | Photostimulation method and apparatus in combination with glucose determination |
US20070149868A1 (en) * | 2002-03-08 | 2007-06-28 | Blank Thomas B | Method and Apparatus for Photostimulation Enhanced Analyte Property Estimation |
DE60337038D1 (en) | 2002-03-22 | 2011-06-16 | Animas Technologies Llc | Performance improvement of an analyte monitoring device |
US6850788B2 (en) | 2002-03-25 | 2005-02-01 | Masimo Corporation | Physiological measurement communications adapter |
CN1327812C (en) * | 2002-03-25 | 2007-07-25 | Tyt技研株式会社 | Noninvasive blood component value measuring instrument and method |
US6654125B2 (en) | 2002-04-04 | 2003-11-25 | Inlight Solutions, Inc | Method and apparatus for optical spectroscopy incorporating a vertical cavity surface emitting laser (VCSEL) as an interferometer reference |
US7027848B2 (en) | 2002-04-04 | 2006-04-11 | Inlight Solutions, Inc. | Apparatus and method for non-invasive spectroscopic measurement of analytes in tissue using a matched reference analyte |
US7486985B2 (en) * | 2002-08-05 | 2009-02-03 | Infraredx, Inc. | Near-infrared spectroscopic analysis of blood vessel walls |
EP1551299A4 (en) * | 2002-08-05 | 2010-01-20 | Infraredx Inc | Near-infrared spectroscopic analysis of blood vessel walls |
US7259906B1 (en) | 2002-09-03 | 2007-08-21 | Cheetah Omni, Llc | System and method for voice control of medical devices |
US7174198B2 (en) * | 2002-12-27 | 2007-02-06 | Igor Trofimov | Non-invasive detection of analytes in a complex matrix |
US6920345B2 (en) | 2003-01-24 | 2005-07-19 | Masimo Corporation | Optical sensor including disposable and reusable elements |
WO2004069164A2 (en) * | 2003-01-30 | 2004-08-19 | Euro Celtique Sa | Wireless blood glucose monitoring system |
US7154592B2 (en) * | 2003-02-11 | 2006-12-26 | Bayer Healthcare Llc. | Multiwavelength readhead for use in the determination of analytes in body fluids |
US20050159656A1 (en) * | 2003-03-07 | 2005-07-21 | Hockersmith Linda J. | Method and apparatus for presentation of noninvasive glucose concentration information |
US7751594B2 (en) * | 2003-04-04 | 2010-07-06 | Lumidigm, Inc. | White-light spectral biometric sensors |
US7460696B2 (en) * | 2004-06-01 | 2008-12-02 | Lumidigm, Inc. | Multispectral imaging biometrics |
US7347365B2 (en) * | 2003-04-04 | 2008-03-25 | Lumidigm, Inc. | Combined total-internal-reflectance and tissue imaging systems and methods |
US7539330B2 (en) * | 2004-06-01 | 2009-05-26 | Lumidigm, Inc. | Multispectral liveness determination |
DE602004030549D1 (en) * | 2003-04-04 | 2011-01-27 | Lumidigm Inc | MULTISPEKTRALBIOMETRIESENSOR |
US7627151B2 (en) * | 2003-04-04 | 2009-12-01 | Lumidigm, Inc. | Systems and methods for improved biometric feature definition |
US7668350B2 (en) * | 2003-04-04 | 2010-02-23 | Lumidigm, Inc. | Comparative texture analysis of tissue for biometric spoof detection |
US7633621B2 (en) * | 2003-04-11 | 2009-12-15 | Thornton Robert L | Method for measurement of analyte concentrations and semiconductor laser-pumped, small-cavity fiber lasers for such measurements and other applications |
US7283242B2 (en) * | 2003-04-11 | 2007-10-16 | Thornton Robert L | Optical spectroscopy apparatus and method for measurement of analyte concentrations or other such species in a specimen employing a semiconductor laser-pumped, small-cavity fiber laser |
US20050092941A1 (en) * | 2003-06-06 | 2005-05-05 | Aventis Pharma Deutschland Gmbh | Method and device for the quantitative analysis of solutions and dispersions by means of near infrared spectroscopy |
US20060097173A1 (en) * | 2003-10-15 | 2006-05-11 | Sanofi-Aventis Deutschland | Method and device for the quantitative analysis of solutions and dispersions by means of near infrared spectroscopy |
US7500950B2 (en) | 2003-07-25 | 2009-03-10 | Masimo Corporation | Multipurpose sensor port |
KR20060082852A (en) | 2003-08-15 | 2006-07-19 | 애니머스 테크놀로지스 엘엘씨 | Microprocessors, devices, and methods for use in monitoring of physiological analytes |
US20070234300A1 (en) * | 2003-09-18 | 2007-10-04 | Leake David W | Method and Apparatus for Performing State-Table Driven Regression Testing |
US20050073690A1 (en) * | 2003-10-03 | 2005-04-07 | Abbink Russell E. | Optical spectroscopy incorporating a vertical cavity surface emitting laser (VCSEL) |
WO2005047834A1 (en) * | 2003-10-15 | 2005-05-26 | Polychromix Corporation | Light processor providing wavelength control and method for same |
US7483729B2 (en) | 2003-11-05 | 2009-01-27 | Masimo Corporation | Pulse oximeter access apparatus and method |
US7889346B2 (en) * | 2003-12-31 | 2011-02-15 | University Of South Carolina | Thin-layer porous optical sensors for gases and other fluids |
GB2410800B (en) | 2004-02-06 | 2007-12-12 | Statoil Asa | Fingerprinting of hydrocarbon containing mixtures |
JP2007527776A (en) | 2004-03-08 | 2007-10-04 | マシモ・コーポレイション | Physiological parameter system |
US8868147B2 (en) * | 2004-04-28 | 2014-10-21 | Glt Acquisition Corp. | Method and apparatus for controlling positioning of a noninvasive analyzer sample probe |
US20080033275A1 (en) * | 2004-04-28 | 2008-02-07 | Blank Thomas B | Method and Apparatus for Sample Probe Movement Control |
US8730047B2 (en) | 2004-05-24 | 2014-05-20 | Trutouch Technologies, Inc. | System for noninvasive determination of analytes in tissue |
US20110178420A1 (en) * | 2010-01-18 | 2011-07-21 | Trent Ridder | Methods and apparatuses for improving breath alcohol testing |
US8515506B2 (en) * | 2004-05-24 | 2013-08-20 | Trutouch Technologies, Inc. | Methods for noninvasive determination of in vivo alcohol concentration using Raman spectroscopy |
US20080319286A1 (en) * | 2004-05-24 | 2008-12-25 | Trent Ridder | Optical Probes for Non-Invasive Analyte Measurements |
US8229185B2 (en) | 2004-06-01 | 2012-07-24 | Lumidigm, Inc. | Hygienic biometric sensors |
US7508965B2 (en) * | 2004-06-01 | 2009-03-24 | Lumidigm, Inc. | System and method for robust fingerprint acquisition |
BRPI0512654A (en) | 2004-07-02 | 2008-03-25 | Bayer Healthcare Llc | light guide test sensor for use in determining an analyte in a fluid sample and methods for manufacturing it |
WO2006020292A2 (en) * | 2004-07-20 | 2006-02-23 | Prescient Medical, Inc. | Systems and methods for medical interventional optical monitoring with molecular filters |
US8787630B2 (en) | 2004-08-11 | 2014-07-22 | Lumidigm, Inc. | Multispectral barcode imaging |
US7522786B2 (en) * | 2005-12-22 | 2009-04-21 | Palo Alto Research Center Incorporated | Transmitting light with photon energy information |
US7310153B2 (en) | 2004-08-23 | 2007-12-18 | Palo Alto Research Center, Incorporated | Using position-sensitive detectors for wavelength determination |
US20070201136A1 (en) * | 2004-09-13 | 2007-08-30 | University Of South Carolina | Thin Film Interference Filter and Bootstrap Method for Interference Filter Thin Film Deposition Process Control |
US20060200070A1 (en) * | 2005-02-14 | 2006-09-07 | Callicoat David N | Method and apparatus for calibrating an analyte detection system with a calibration sample |
DE102005007755B4 (en) * | 2005-02-18 | 2007-10-18 | Betriebsforschungsinstitut VDEh - Institut für angewandte Forschung GmbH | Method for analyzing the composition of a liquid molten metal |
ATE468808T1 (en) | 2005-03-01 | 2010-06-15 | Masimo Laboratories Inc | NON-INVASIVE MULTIPARAMETER PATIENT MONITOR |
US20060206018A1 (en) * | 2005-03-04 | 2006-09-14 | Alan Abul-Haj | Method and apparatus for noninvasive targeting |
EP1874178A4 (en) | 2005-04-13 | 2009-12-09 | Glucolight Corp | Method for data reduction and calibration of an oct-based blood glucose monitor |
US7801338B2 (en) | 2005-04-27 | 2010-09-21 | Lumidigm, Inc. | Multispectral biometric sensors |
US7409239B2 (en) * | 2005-05-05 | 2008-08-05 | The Hong Kong Polytechnic University | Method for predicting the blood glucose level of a person |
EP1897486A1 (en) * | 2006-09-11 | 2008-03-12 | FOSS Analytical AB | Optical blood analyte monitor |
US20060281982A1 (en) * | 2005-06-14 | 2006-12-14 | Diasense, Inc. | Method and apparatus for the non-invasive sensing of glucose in a human subject |
US8140139B2 (en) | 2005-06-14 | 2012-03-20 | Dominion Assets, Llc | Method and apparatus for the non-invasive sensing of glucose in a human subject |
US7962188B2 (en) | 2005-10-14 | 2011-06-14 | Masimo Corporation | Robust alarm system |
US7519253B2 (en) | 2005-11-18 | 2009-04-14 | Omni Sciences, Inc. | Broadband or mid-infrared fiber light sources |
WO2007064575A1 (en) * | 2005-11-28 | 2007-06-07 | Ometric Corporation | Optical analysis system and method for real time multivariate optical computing |
WO2007061436A1 (en) * | 2005-11-28 | 2007-05-31 | University Of South Carolina | Self calibration methods for optical analysis system |
EP1974201A1 (en) * | 2005-11-28 | 2008-10-01 | University of South Carolina | Optical analysis system for dynamic, real-time detection and measurement |
WO2007064578A2 (en) * | 2005-11-28 | 2007-06-07 | University Of South Carolina | Optical analysis system and optical train |
US20070166245A1 (en) * | 2005-11-28 | 2007-07-19 | Leonard Mackles | Propellant free foamable toothpaste composition |
US7920258B2 (en) * | 2005-11-28 | 2011-04-05 | Halliburton Energy Services, Inc. | Optical analysis system and elements to isolate spectral region |
WO2007062202A1 (en) * | 2005-11-28 | 2007-05-31 | University Of South Carolina | Novel multivariate optical elements for optical analysis system |
EP2399515A3 (en) | 2005-11-30 | 2012-10-17 | Toshiba Medical Systems Corporation | Method for noninvasive measurement of glucose and apparatus for noninvasive measurement of glucose |
US7358476B2 (en) * | 2005-12-22 | 2008-04-15 | Palo Alto Research Center Incorporated | Sensing photons from objects in channels |
US7547904B2 (en) * | 2005-12-22 | 2009-06-16 | Palo Alto Research Center Incorporated | Sensing photon energies emanating from channels or moving objects |
US7315667B2 (en) | 2005-12-22 | 2008-01-01 | Palo Alto Research Center Incorporated | Propagating light to be sensed |
US8437582B2 (en) | 2005-12-22 | 2013-05-07 | Palo Alto Research Center Incorporated | Transmitting light with lateral variation |
US7433552B2 (en) * | 2005-12-22 | 2008-10-07 | Palo Alto Research Center Incorporated | Obtaining analyte information |
US7420677B2 (en) * | 2005-12-22 | 2008-09-02 | Palo Alto Research Center Incorporated | Sensing photon energies of optical signals |
US8182443B1 (en) | 2006-01-17 | 2012-05-22 | Masimo Corporation | Drug administration controller |
US7492372B2 (en) * | 2006-02-21 | 2009-02-17 | Bio-Rad Laboratories, Inc. | Overlap density (OD) heatmaps and consensus data displays |
US7623233B2 (en) | 2006-03-10 | 2009-11-24 | Ometric Corporation | Optical analysis systems and methods for dynamic, high-speed detection and real-time multivariate optical computing |
US8219172B2 (en) | 2006-03-17 | 2012-07-10 | Glt Acquisition Corp. | System and method for creating a stable optical interface |
US8027855B2 (en) * | 2006-05-30 | 2011-09-27 | Halliburton Energy Services Inc. | Methods of assessing and designing an application specific measurement system |
US10188348B2 (en) | 2006-06-05 | 2019-01-29 | Masimo Corporation | Parameter upgrade system |
WO2008002903A2 (en) | 2006-06-26 | 2008-01-03 | University Of South Carolina | Data validation and classification in optical analysis systems |
US8175346B2 (en) | 2006-07-19 | 2012-05-08 | Lumidigm, Inc. | Whole-hand multispectral biometric imaging |
US7899217B2 (en) * | 2006-07-19 | 2011-03-01 | Lumidign, Inc. | Multibiometric multispectral imager |
US8355545B2 (en) | 2007-04-10 | 2013-01-15 | Lumidigm, Inc. | Biometric detection using spatial, temporal, and/or spectral techniques |
US7995808B2 (en) | 2006-07-19 | 2011-08-09 | Lumidigm, Inc. | Contactless multispectral biometric capture |
US7801339B2 (en) | 2006-07-31 | 2010-09-21 | Lumidigm, Inc. | Biometrics with spatiospectral spoof detection |
US7804984B2 (en) | 2006-07-31 | 2010-09-28 | Lumidigm, Inc. | Spatial-spectral fingerprint spoof detection |
US8457707B2 (en) | 2006-09-20 | 2013-06-04 | Masimo Corporation | Congenital heart disease monitor |
US8840549B2 (en) | 2006-09-22 | 2014-09-23 | Masimo Corporation | Modular patient monitor |
CA2664691A1 (en) * | 2006-09-29 | 2008-04-03 | Ottawa Health Research Institute | Correlation technique for analysis of clinical condition |
US8255026B1 (en) | 2006-10-12 | 2012-08-28 | Masimo Corporation, Inc. | Patient monitor capable of monitoring the quality of attached probes and accessories |
JP2010506614A (en) | 2006-10-12 | 2010-03-04 | マシモ コーポレイション | Perfusion index smoothing device |
US7880626B2 (en) | 2006-10-12 | 2011-02-01 | Masimo Corporation | System and method for monitoring the life of a physiological sensor |
US9861305B1 (en) | 2006-10-12 | 2018-01-09 | Masimo Corporation | Method and apparatus for calibration to reduce coupling between signals in a measurement system |
US9182282B2 (en) * | 2006-11-02 | 2015-11-10 | Halliburton Energy Services, Inc. | Multi-analyte optical computing system |
US8379199B2 (en) | 2006-11-02 | 2013-02-19 | Halliburton Energy Services, Inc. | Self-contained multivariate optical computing and analysis system |
US7718948B2 (en) * | 2006-12-04 | 2010-05-18 | Palo Alto Research Center Incorporated | Monitoring light pulses |
US8414499B2 (en) | 2006-12-09 | 2013-04-09 | Masimo Corporation | Plethysmograph variability processor |
CN100449302C (en) * | 2007-01-15 | 2009-01-07 | 浙江大学 | Quickly non-demage discriminating method and device for marked wine year of bottled yellow rice or millet wine |
WO2008089282A2 (en) | 2007-01-16 | 2008-07-24 | Silver James H | Sensors for detecting subtances indicative of stroke, ischemia, infection or inflammation |
US8652060B2 (en) | 2007-01-20 | 2014-02-18 | Masimo Corporation | Perfusion trend indicator |
US9164037B2 (en) | 2007-01-26 | 2015-10-20 | Palo Alto Research Center Incorporated | Method and system for evaluation of signals received from spatially modulated excitation and emission to accurately determine particle positions and distances |
US8821799B2 (en) | 2007-01-26 | 2014-09-02 | Palo Alto Research Center Incorporated | Method and system implementing spatially modulated excitation or emission for particle characterization with enhanced sensitivity |
US7502123B2 (en) * | 2007-02-05 | 2009-03-10 | Palo Alto Research Center Incorporated | Obtaining information from optical cavity output light |
US7633629B2 (en) * | 2007-02-05 | 2009-12-15 | Palo Alto Research Center Incorporated | Tuning optical cavities |
US7852490B2 (en) * | 2007-02-05 | 2010-12-14 | Palo Alto Research Center Incorporated | Implanting optical cavity structures |
US7936463B2 (en) | 2007-02-05 | 2011-05-03 | Palo Alto Research Center Incorporated | Containing analyte in optical cavity structures |
US7817276B2 (en) * | 2007-02-05 | 2010-10-19 | Palo Alto Research Center Incorporated | Distinguishing objects |
US7817281B2 (en) * | 2007-02-05 | 2010-10-19 | Palo Alto Research Center Incorporated | Tuning optical cavities |
US8285010B2 (en) | 2007-03-21 | 2012-10-09 | Lumidigm, Inc. | Biometrics based on locally consistent features |
WO2008121692A1 (en) * | 2007-03-30 | 2008-10-09 | University Of South Carolina | Tablet analysis and measurement system |
WO2008121684A1 (en) * | 2007-03-30 | 2008-10-09 | University Of South Carolina | Novel multi-analyte optical computing system |
US8212216B2 (en) * | 2007-03-30 | 2012-07-03 | Halliburton Energy Services, Inc. | In-line process measurement systems and methods |
US8374665B2 (en) | 2007-04-21 | 2013-02-12 | Cercacor Laboratories, Inc. | Tissue profile wellness monitor |
US20090036759A1 (en) * | 2007-08-01 | 2009-02-05 | Ault Timothy E | Collapsible noninvasive analyzer method and apparatus |
US8283633B2 (en) * | 2007-11-30 | 2012-10-09 | Halliburton Energy Services, Inc. | Tuning D* with modified thermal detectors |
US8320983B2 (en) * | 2007-12-17 | 2012-11-27 | Palo Alto Research Center Incorporated | Controlling transfer of objects affecting optical characteristics |
US7817254B2 (en) * | 2008-01-30 | 2010-10-19 | Palo Alto Research Center Incorporated | Obtaining information from time variation of sensing results |
US8153949B2 (en) * | 2008-12-18 | 2012-04-10 | Palo Alto Research Center Incorporated | Obtaining sensing results indicating time variation |
US8263955B2 (en) * | 2008-12-18 | 2012-09-11 | Palo Alto Research Center Incorporated | Causing relative motion |
US8153950B2 (en) * | 2008-12-18 | 2012-04-10 | Palo Alto Research Center Incorporated | Obtaining sensing results and/or data in response to object detection |
US7894068B2 (en) * | 2008-02-04 | 2011-02-22 | Palo Alto Research Center Incorporated | Producing filters with combined transmission and/or reflection functions |
US8373860B2 (en) * | 2008-02-01 | 2013-02-12 | Palo Alto Research Center Incorporated | Transmitting/reflecting emanating light with time variation |
US8629981B2 (en) | 2008-02-01 | 2014-01-14 | Palo Alto Research Center Incorporated | Analyzers with time variation based on color-coded spatial modulation |
WO2009111542A2 (en) | 2008-03-04 | 2009-09-11 | Glucolight Corporation | Methods and systems for analyte level estimation in optical coherence tomography |
US8212213B2 (en) * | 2008-04-07 | 2012-07-03 | Halliburton Energy Services, Inc. | Chemically-selective detector and methods relating thereto |
TWI394580B (en) | 2008-04-28 | 2013-05-01 | Halozyme Inc | Super fast-acting insulin compositions |
WO2009134724A1 (en) | 2008-05-02 | 2009-11-05 | Masimo Corporation | Monitor configuration system |
US9107625B2 (en) | 2008-05-05 | 2015-08-18 | Masimo Corporation | Pulse oximetry system with electrical decoupling circuitry |
US7897923B2 (en) * | 2008-06-28 | 2011-03-01 | The Boeing Company | Sample preparation and methods for portable IR spectroscopy measurements of UV and thermal effect |
US8519337B2 (en) * | 2008-06-28 | 2013-08-27 | The Boeing Company | Thermal effect measurement with near-infrared spectroscopy |
EP2326239B1 (en) | 2008-07-03 | 2017-06-21 | Masimo Laboratories, Inc. | Protrusion for improving spectroscopic measurement of blood constituents |
US20100030040A1 (en) | 2008-08-04 | 2010-02-04 | Masimo Laboratories, Inc. | Multi-stream data collection system for noninvasive measurement of blood constituents |
US8552382B2 (en) * | 2008-08-14 | 2013-10-08 | The Boeing Company | Thermal effect measurement with mid-infrared spectroscopy |
SE532941C2 (en) | 2008-09-15 | 2010-05-18 | Phasein Ab | Gas sampling line for breathing gases |
US8771204B2 (en) | 2008-12-30 | 2014-07-08 | Masimo Corporation | Acoustic sensor assembly |
US8588880B2 (en) | 2009-02-16 | 2013-11-19 | Masimo Corporation | Ear sensor |
US10007758B2 (en) | 2009-03-04 | 2018-06-26 | Masimo Corporation | Medical monitoring system |
US10032002B2 (en) | 2009-03-04 | 2018-07-24 | Masimo Corporation | Medical monitoring system |
EP3605550A1 (en) | 2009-03-04 | 2020-02-05 | Masimo Corporation | Medical monitoring system |
US9323894B2 (en) | 2011-08-19 | 2016-04-26 | Masimo Corporation | Health care sanitation monitoring system |
US8388353B2 (en) | 2009-03-11 | 2013-03-05 | Cercacor Laboratories, Inc. | Magnetic connector |
US7896498B2 (en) * | 2009-03-30 | 2011-03-01 | Ottawa Hospital Research Institute | Apparatus and method for optical measurements |
US8571619B2 (en) | 2009-05-20 | 2013-10-29 | Masimo Corporation | Hemoglobin display and patient treatment |
US8473020B2 (en) | 2009-07-29 | 2013-06-25 | Cercacor Laboratories, Inc. | Non-invasive physiological sensor cover |
WO2011028620A1 (en) | 2009-08-26 | 2011-03-10 | Lumidigm, Inc. | Multiplexed biometric imaging and dual-imager biometric sensor |
US20110137297A1 (en) | 2009-09-17 | 2011-06-09 | Kiani Massi Joe E | Pharmacological management system |
US20110082711A1 (en) | 2009-10-06 | 2011-04-07 | Masimo Laboratories, Inc. | Personal digital assistant or organizer for monitoring glucose levels |
US8823802B2 (en) * | 2009-10-15 | 2014-09-02 | University Of South Carolina | Multi-mode imaging in the thermal infrared for chemical contrast enhancement |
US9839381B1 (en) | 2009-11-24 | 2017-12-12 | Cercacor Laboratories, Inc. | Physiological measurement system with automatic wavelength adjustment |
WO2011069122A1 (en) | 2009-12-04 | 2011-06-09 | Masimo Corporation | Calibration for multi-stage physiological monitors |
US9153112B1 (en) | 2009-12-21 | 2015-10-06 | Masimo Corporation | Modular patient monitor |
WO2011091059A1 (en) | 2010-01-19 | 2011-07-28 | Masimo Corporation | Wellness analysis system |
JP2013521054A (en) | 2010-03-01 | 2013-06-10 | マシモ コーポレイション | Adaptive alarm system |
US8584345B2 (en) | 2010-03-08 | 2013-11-19 | Masimo Corporation | Reprocessing of a physiological sensor |
US8570149B2 (en) | 2010-03-16 | 2013-10-29 | Lumidigm, Inc. | Biometric imaging using an optical adaptive interface |
US9307928B1 (en) | 2010-03-30 | 2016-04-12 | Masimo Corporation | Plethysmographic respiration processor |
US8666468B1 (en) | 2010-05-06 | 2014-03-04 | Masimo Corporation | Patient monitor for determining microcirculation state |
US8330109B2 (en) * | 2010-09-02 | 2012-12-11 | The Boeing Company | Method for determining contamination of material using Mid-IR spectroscopy |
WO2012050847A2 (en) | 2010-09-28 | 2012-04-19 | Masimo Corporation | Depth of consciousness monitor including oximeter |
US9211095B1 (en) | 2010-10-13 | 2015-12-15 | Masimo Corporation | Physiological measurement logic engine |
US20120226117A1 (en) | 2010-12-01 | 2012-09-06 | Lamego Marcelo M | Handheld processing device including medical applications for minimally and non invasive glucose measurements |
JP5591680B2 (en) * | 2010-12-21 | 2014-09-17 | 株式会社フォトサイエンス | Cholesterol concentration measuring device |
EP2673721A1 (en) | 2011-02-13 | 2013-12-18 | Masimo Corporation | Medical characterization system |
US8527212B2 (en) | 2011-02-14 | 2013-09-03 | Honeywell Asca Inc. | Increased absorption-measurement accuracy through windowing of photon-transit times to account for scattering in continuous webs and powders |
US9066666B2 (en) | 2011-02-25 | 2015-06-30 | Cercacor Laboratories, Inc. | Patient monitor for monitoring microcirculation |
US9993529B2 (en) | 2011-06-17 | 2018-06-12 | Halozyme, Inc. | Stable formulations of a hyaluronan-degrading enzyme |
KR101676543B1 (en) | 2011-06-17 | 2016-11-15 | 할로자임, 아이엔씨 | Continuous Subcutaneous Insulin Infusion Methods with a Hyaluronan Degrading Enzyme |
US9532722B2 (en) | 2011-06-21 | 2017-01-03 | Masimo Corporation | Patient monitoring system |
US9986919B2 (en) | 2011-06-21 | 2018-06-05 | Masimo Corporation | Patient monitoring system |
US11439329B2 (en) | 2011-07-13 | 2022-09-13 | Masimo Corporation | Multiple measurement mode in a physiological sensor |
US8723140B2 (en) | 2011-08-09 | 2014-05-13 | Palo Alto Research Center Incorporated | Particle analyzer with spatial modulation and long lifetime bioprobes |
US9029800B2 (en) | 2011-08-09 | 2015-05-12 | Palo Alto Research Center Incorporated | Compact analyzer with spatial modulation and multiple intensity modulated excitation sources |
US9782077B2 (en) | 2011-08-17 | 2017-10-10 | Masimo Corporation | Modulated physiological sensor |
US9808188B1 (en) | 2011-10-13 | 2017-11-07 | Masimo Corporation | Robust fractional saturation determination |
US9943269B2 (en) | 2011-10-13 | 2018-04-17 | Masimo Corporation | System for displaying medical monitoring data |
WO2013056160A2 (en) | 2011-10-13 | 2013-04-18 | Masimo Corporation | Medical monitoring hub |
US9778079B1 (en) | 2011-10-27 | 2017-10-03 | Masimo Corporation | Physiological monitor gauge panel |
US11172890B2 (en) | 2012-01-04 | 2021-11-16 | Masimo Corporation | Automated condition screening and detection |
US9392945B2 (en) | 2012-01-04 | 2016-07-19 | Masimo Corporation | Automated CCHD screening and detection |
US10149616B2 (en) | 2012-02-09 | 2018-12-11 | Masimo Corporation | Wireless patient monitoring device |
WO2013148605A1 (en) | 2012-03-25 | 2013-10-03 | Masimo Corporation | Physiological monitor touchscreen interface |
JP6490577B2 (en) | 2012-04-17 | 2019-03-27 | マシモ・コーポレイション | How to operate a pulse oximeter device |
US9585604B2 (en) | 2012-07-16 | 2017-03-07 | Zyomed Corp. | Multiplexed pathlength resolved noninvasive analyzer apparatus with dynamic optical paths and method of use thereof |
US9351671B2 (en) | 2012-07-16 | 2016-05-31 | Timothy Ruchti | Multiplexed pathlength resolved noninvasive analyzer apparatus and method of use thereof |
US9351672B2 (en) | 2012-07-16 | 2016-05-31 | Timothy Ruchti | Multiplexed pathlength resolved noninvasive analyzer apparatus with stacked filters and method of use thereof |
US20150018642A1 (en) | 2013-07-12 | 2015-01-15 | Sandeep Gulati | Tissue pathlength resolved noninvasive analyzer apparatus and method of use thereof |
US9697928B2 (en) | 2012-08-01 | 2017-07-04 | Masimo Corporation | Automated assembly sensor cable |
US9955937B2 (en) | 2012-09-20 | 2018-05-01 | Masimo Corporation | Acoustic patient sensor coupler |
US9749232B2 (en) | 2012-09-20 | 2017-08-29 | Masimo Corporation | Intelligent medical network edge router |
US9877650B2 (en) | 2012-09-20 | 2018-01-30 | Masimo Corporation | Physiological monitor with mobile computing device connectivity |
RU2520940C2 (en) * | 2012-10-05 | 2014-06-27 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Новосибирский национальный исследовательский государственный университет" (Новосибирский государственный университет, НГУ) | Apparatus for monitoring parameters of ion beam |
US9560996B2 (en) | 2012-10-30 | 2017-02-07 | Masimo Corporation | Universal medical system |
US9787568B2 (en) | 2012-11-05 | 2017-10-10 | Cercacor Laboratories, Inc. | Physiological test credit method |
US10660526B2 (en) | 2012-12-31 | 2020-05-26 | Omni Medsci, Inc. | Near-infrared time-of-flight imaging using laser diodes with Bragg reflectors |
EP2938259A4 (en) | 2012-12-31 | 2016-08-17 | Omni Medsci Inc | Near-infrared lasers for non-invasive monitoring of glucose, ketones, hba1c, and other blood constituents |
WO2014105521A1 (en) | 2012-12-31 | 2014-07-03 | Omni Medsci, Inc. | Short-wave infrared super-continuum lasers for early detection of dental caries |
US9500635B2 (en) | 2012-12-31 | 2016-11-22 | Omni Medsci, Inc. | Short-wave infrared super-continuum lasers for early detection of dental caries |
US9993159B2 (en) | 2012-12-31 | 2018-06-12 | Omni Medsci, Inc. | Near-infrared super-continuum lasers for early detection of breast and other cancers |
WO2014143276A2 (en) | 2012-12-31 | 2014-09-18 | Omni Medsci, Inc. | Short-wave infrared super-continuum lasers for natural gas leak detection, exploration, and other active remote sensing applications |
US9724025B1 (en) | 2013-01-16 | 2017-08-08 | Masimo Corporation | Active-pulse blood analysis system |
US9965946B2 (en) | 2013-03-13 | 2018-05-08 | Masimo Corporation | Systems and methods for monitoring a patient health network |
US9936917B2 (en) | 2013-03-14 | 2018-04-10 | Masimo Laboratories, Inc. | Patient monitor placement indicator |
JP6116956B2 (en) * | 2013-03-22 | 2017-04-19 | パナソニックヘルスケアホールディングス株式会社 | Quantitative determination method and apparatus for glucose concentration |
US9891079B2 (en) | 2013-07-17 | 2018-02-13 | Masimo Corporation | Pulser with double-bearing position encoder for non-invasive physiological monitoring |
US10555678B2 (en) | 2013-08-05 | 2020-02-11 | Masimo Corporation | Blood pressure monitor with valve-chamber assembly |
CN103434647A (en) * | 2013-09-11 | 2013-12-11 | 中国民航大学 | Airplane residual ice monitoring device capable of eliminating environment interference |
WO2015038683A2 (en) | 2013-09-12 | 2015-03-19 | Cercacor Laboratories, Inc. | Medical device management system |
WO2015054166A1 (en) | 2013-10-07 | 2015-04-16 | Masimo Corporation | Regional oximetry pod |
US11147518B1 (en) | 2013-10-07 | 2021-10-19 | Masimo Corporation | Regional oximetry signal processor |
US10832818B2 (en) | 2013-10-11 | 2020-11-10 | Masimo Corporation | Alarm notification system |
US10279247B2 (en) | 2013-12-13 | 2019-05-07 | Masimo Corporation | Avatar-incentive healthcare therapy |
US10213550B2 (en) | 2014-01-23 | 2019-02-26 | Covidien Lp | Systems and methods for monitoring clinical procedures using regional blood oxygen saturation |
US9867561B2 (en) | 2014-01-27 | 2018-01-16 | Covidien Lp | Systems and methods for determining whether regional oximetry sensors are properly positioned |
US11259745B2 (en) | 2014-01-28 | 2022-03-01 | Masimo Corporation | Autonomous drug delivery system |
US9861317B2 (en) | 2014-02-20 | 2018-01-09 | Covidien Lp | Methods and systems for determining regional blood oxygen saturation |
CN103870999A (en) * | 2014-02-25 | 2014-06-18 | 国家电网公司 | Rotated empirical orthogonal decomposition-based irradiance area division method |
JP6323060B2 (en) * | 2014-02-25 | 2018-05-16 | セイコーエプソン株式会社 | Component analyzer, component analysis method |
US10123729B2 (en) | 2014-06-13 | 2018-11-13 | Nanthealth, Inc. | Alarm fatigue management systems and methods |
US10231670B2 (en) | 2014-06-19 | 2019-03-19 | Masimo Corporation | Proximity sensor in pulse oximeter |
CN104034704A (en) * | 2014-06-27 | 2014-09-10 | 无锡利弗莫尔仪器有限公司 | Method and device for improving infrared radiation imaging resolution ratio |
EP3172487B1 (en) | 2014-07-23 | 2020-10-21 | Ascensia Diabetes Care Holdings AG | Light switching indicators by wavelength filtration |
US10111591B2 (en) | 2014-08-26 | 2018-10-30 | Nanthealth, Inc. | Real-time monitoring systems and methods in a healthcare environment |
WO2016036985A1 (en) | 2014-09-04 | 2016-03-10 | Masimo Corportion | Total hemoglobin index system |
US10506989B2 (en) | 2014-09-05 | 2019-12-17 | Phc Holdings Corporation | Method for quantifying glucose concentration and glucose concentration measurement device |
US10383520B2 (en) | 2014-09-18 | 2019-08-20 | Masimo Semiconductor, Inc. | Enhanced visible near-infrared photodiode and non-invasive physiological sensor |
WO2016054079A1 (en) | 2014-09-29 | 2016-04-07 | Zyomed Corp. | Systems and methods for blood glucose and other analyte detection and measurement using collision computing |
WO2016057553A1 (en) | 2014-10-07 | 2016-04-14 | Masimo Corporation | Modular physiological sensors |
JP6535461B2 (en) * | 2014-12-16 | 2019-06-26 | 株式会社トプコン | Material analysis sensor and material analysis device |
KR102335739B1 (en) | 2014-12-19 | 2021-12-06 | 삼성전자주식회사 | Apparatus and method for measuring a blood glucose in a noninvasive manner |
US10328202B2 (en) | 2015-02-04 | 2019-06-25 | Covidien Lp | Methods and systems for determining fluid administration |
KR20230170116A (en) | 2015-02-06 | 2023-12-18 | 마시모 코오퍼레이션 | Fold flex circuit for optical probes |
US10568553B2 (en) | 2015-02-06 | 2020-02-25 | Masimo Corporation | Soft boot pulse oximetry sensor |
US10205291B2 (en) | 2015-02-06 | 2019-02-12 | Masimo Corporation | Pogo pin connector |
US9885147B2 (en) | 2015-04-24 | 2018-02-06 | University Of South Carolina | Reproducible sample preparation method for quantitative stain detection |
US10041866B2 (en) | 2015-04-24 | 2018-08-07 | University Of South Carolina | Reproducible sample preparation method for quantitative stain detection |
US10524738B2 (en) | 2015-05-04 | 2020-01-07 | Cercacor Laboratories, Inc. | Noninvasive sensor system with visual infographic display |
WO2016191307A1 (en) | 2015-05-22 | 2016-12-01 | Cercacor Laboratories, Inc. | Non-invasive optical physiological differential pathlength sensor |
CA2994172A1 (en) | 2015-08-11 | 2017-02-16 | Masimo Corporation | Medical monitoring analysis and replay including indicia responsive to light attenuated by body tissue |
CN113367671A (en) | 2015-08-31 | 2021-09-10 | 梅西莫股份有限公司 | Wireless patient monitoring system and method |
US11504066B1 (en) | 2015-09-04 | 2022-11-22 | Cercacor Laboratories, Inc. | Low-noise sensor system |
US11679579B2 (en) | 2015-12-17 | 2023-06-20 | Masimo Corporation | Varnish-coated release liner |
US10537285B2 (en) | 2016-03-04 | 2020-01-21 | Masimo Corporation | Nose sensor |
US10993662B2 (en) | 2016-03-04 | 2021-05-04 | Masimo Corporation | Nose sensor |
WO2017160766A1 (en) * | 2016-03-14 | 2017-09-21 | Analog Devices, Inc. | Optical evaluation of skin type and condition |
US9554738B1 (en) | 2016-03-30 | 2017-01-31 | Zyomed Corp. | Spectroscopic tomography systems and methods for noninvasive detection and measurement of analytes using collision computing |
US11191484B2 (en) | 2016-04-29 | 2021-12-07 | Masimo Corporation | Optical sensor tape |
CN106066981B (en) * | 2016-06-01 | 2018-08-24 | 上海慧银信息科技有限公司 | Scanning head |
WO2018009612A1 (en) | 2016-07-06 | 2018-01-11 | Patient Doctor Technologies, Inc. | Secure and zero knowledge data sharing for cloud applications |
US10617302B2 (en) | 2016-07-07 | 2020-04-14 | Masimo Corporation | Wearable pulse oximeter and respiration monitor |
KR102539142B1 (en) | 2016-09-05 | 2023-06-01 | 삼성전자주식회사 | Device and method for analysis of spectra, and device for measurement the blood glucose |
EP3525661A1 (en) | 2016-10-13 | 2019-08-21 | Masimo Corporation | Systems and methods for patient fall detection |
US11504058B1 (en) | 2016-12-02 | 2022-11-22 | Masimo Corporation | Multi-site noninvasive measurement of a physiological parameter |
US10750984B2 (en) | 2016-12-22 | 2020-08-25 | Cercacor Laboratories, Inc. | Methods and devices for detecting intensity of light with translucent detector |
CN106706523A (en) * | 2017-01-13 | 2017-05-24 | 清华大学 | Near-infrared spectrometer based on upconversion material |
US10721785B2 (en) | 2017-01-18 | 2020-07-21 | Masimo Corporation | Patient-worn wireless physiological sensor with pairing functionality |
US10388120B2 (en) | 2017-02-24 | 2019-08-20 | Masimo Corporation | Localized projection of audible noises in medical settings |
US11086609B2 (en) | 2017-02-24 | 2021-08-10 | Masimo Corporation | Medical monitoring hub |
WO2018156648A1 (en) | 2017-02-24 | 2018-08-30 | Masimo Corporation | Managing dynamic licenses for physiological parameters in a patient monitoring environment |
US20180247712A1 (en) | 2017-02-24 | 2018-08-30 | Masimo Corporation | System for displaying medical monitoring data |
WO2018156809A1 (en) | 2017-02-24 | 2018-08-30 | Masimo Corporation | Augmented reality system for displaying patient data |
US10327713B2 (en) | 2017-02-24 | 2019-06-25 | Masimo Corporation | Modular multi-parameter patient monitoring device |
US11185262B2 (en) | 2017-03-10 | 2021-11-30 | Masimo Corporation | Pneumonia screener |
WO2018194992A1 (en) | 2017-04-18 | 2018-10-25 | Masimo Corporation | Nose sensor |
US10918281B2 (en) | 2017-04-26 | 2021-02-16 | Masimo Corporation | Medical monitoring device having multiple configurations |
KR102615025B1 (en) | 2017-04-28 | 2023-12-18 | 마시모 코오퍼레이션 | Spot check measurement system |
JP7159208B2 (en) | 2017-05-08 | 2022-10-24 | マシモ・コーポレイション | A system for pairing a medical system with a network controller by using a dongle |
TWI806869B (en) | 2017-05-22 | 2023-07-01 | 立陶宛商布羅利思感測科技公司 | Tunable hybrid iii-v/ iv laser sensor system-on-a-chip for real-time monitoring of a blood constituent concentration level, and methods of manufacturing and using the same |
WO2019014629A1 (en) | 2017-07-13 | 2019-01-17 | Cercacor Laboratories, Inc. | Medical monitoring device for harmonizing physiological measurements |
KR102611362B1 (en) | 2017-08-15 | 2023-12-08 | 마시모 코오퍼레이션 | Waterproof connector for non-invasive patient monitors |
KR20200074175A (en) | 2017-10-19 | 2020-06-24 | 마시모 코오퍼레이션 | Display configuration for medical monitoring systems |
USD925597S1 (en) | 2017-10-31 | 2021-07-20 | Masimo Corporation | Display screen or portion thereof with graphical user interface |
WO2019089655A1 (en) | 2017-10-31 | 2019-05-09 | Masimo Corporation | System for displaying oxygen state indications |
TWI662261B (en) * | 2018-01-17 | 2019-06-11 | 國立交通大學 | Coaxial heterogeneous hyperspectral system |
US11766198B2 (en) | 2018-02-02 | 2023-09-26 | Cercacor Laboratories, Inc. | Limb-worn patient monitoring device |
CN112075000A (en) | 2018-02-02 | 2020-12-11 | 布罗利思感测科技公司 | Widely tunable laser and wavelength determination of laser system thereof |
WO2019177941A1 (en) | 2018-03-14 | 2019-09-19 | Google Llc | Fourier-transform infrared (ft-ir) spectroscopy using a mobile device |
WO2019204368A1 (en) | 2018-04-19 | 2019-10-24 | Masimo Corporation | Mobile patient alarm display |
WO2019209915A1 (en) | 2018-04-24 | 2019-10-31 | Cercacor Laboratories, Inc. | Easy insert finger sensor for transmission based spectroscopy sensor |
US10932729B2 (en) | 2018-06-06 | 2021-03-02 | Masimo Corporation | Opioid overdose monitoring |
US10779098B2 (en) | 2018-07-10 | 2020-09-15 | Masimo Corporation | Patient monitor alarm speaker analyzer |
US11872156B2 (en) | 2018-08-22 | 2024-01-16 | Masimo Corporation | Core body temperature measurement |
USD998630S1 (en) | 2018-10-11 | 2023-09-12 | Masimo Corporation | Display screen or portion thereof with a graphical user interface |
BR112021006841A2 (en) | 2018-10-11 | 2021-07-13 | Masimo Corporation | non-invasive physiological sensor assembly and method of fabricating a connector assembly for a non-invasive sensor assembly |
USD917564S1 (en) | 2018-10-11 | 2021-04-27 | Masimo Corporation | Display screen or portion thereof with graphical user interface |
US11389093B2 (en) | 2018-10-11 | 2022-07-19 | Masimo Corporation | Low noise oximetry cable |
USD998631S1 (en) | 2018-10-11 | 2023-09-12 | Masimo Corporation | Display screen or portion thereof with a graphical user interface |
USD917550S1 (en) | 2018-10-11 | 2021-04-27 | Masimo Corporation | Display screen or portion thereof with a graphical user interface |
USD916135S1 (en) | 2018-10-11 | 2021-04-13 | Masimo Corporation | Display screen or portion thereof with a graphical user interface |
US11406286B2 (en) | 2018-10-11 | 2022-08-09 | Masimo Corporation | Patient monitoring device with improved user interface |
USD999246S1 (en) | 2018-10-11 | 2023-09-19 | Masimo Corporation | Display screen or portion thereof with a graphical user interface |
US11464410B2 (en) | 2018-10-12 | 2022-10-11 | Masimo Corporation | Medical systems and methods |
USD897098S1 (en) | 2018-10-12 | 2020-09-29 | Masimo Corporation | Card holder set |
WO2020077149A1 (en) | 2018-10-12 | 2020-04-16 | Masimo Corporation | System for transmission of sensor data using dual communication protocol |
US11684296B2 (en) | 2018-12-21 | 2023-06-27 | Cercacor Laboratories, Inc. | Noninvasive physiological sensor |
CN109781681A (en) * | 2019-01-14 | 2019-05-21 | 广州大学 | A kind of fluorescence quantum yield tester and its test method |
US20210022628A1 (en) | 2019-04-17 | 2021-01-28 | Masimo Corporation | Patient monitoring systems, devices, and methods |
USD917704S1 (en) | 2019-08-16 | 2021-04-27 | Masimo Corporation | Patient monitor |
USD985498S1 (en) | 2019-08-16 | 2023-05-09 | Masimo Corporation | Connector |
USD919100S1 (en) | 2019-08-16 | 2021-05-11 | Masimo Corporation | Holder for a patient monitor |
USD921202S1 (en) | 2019-08-16 | 2021-06-01 | Masimo Corporation | Holder for a blood pressure device |
USD919094S1 (en) | 2019-08-16 | 2021-05-11 | Masimo Corporation | Blood pressure device |
US11832940B2 (en) | 2019-08-27 | 2023-12-05 | Cercacor Laboratories, Inc. | Non-invasive medical monitoring device for blood analyte measurements |
USD927699S1 (en) | 2019-10-18 | 2021-08-10 | Masimo Corporation | Electrode pad |
KR20220083771A (en) | 2019-10-18 | 2022-06-20 | 마시모 코오퍼레이션 | Display layouts and interactive objects for patient monitoring |
US11879960B2 (en) | 2020-02-13 | 2024-01-23 | Masimo Corporation | System and method for monitoring clinical activities |
US11721105B2 (en) | 2020-02-13 | 2023-08-08 | Masimo Corporation | System and method for monitoring clinical activities |
WO2021188999A2 (en) | 2020-03-20 | 2021-09-23 | Masimo Corporation | Health monitoring system for limiting the spread of an infection in an organization |
USD933232S1 (en) | 2020-05-11 | 2021-10-12 | Masimo Corporation | Blood pressure monitor |
USD979516S1 (en) | 2020-05-11 | 2023-02-28 | Masimo Corporation | Connector |
USD974193S1 (en) | 2020-07-27 | 2023-01-03 | Masimo Corporation | Wearable temperature measurement device |
USD980091S1 (en) | 2020-07-27 | 2023-03-07 | Masimo Corporation | Wearable temperature measurement device |
CN112087663B (en) * | 2020-09-10 | 2021-09-28 | 北京小糖科技有限责任公司 | Method for generating dance video with adaptive light and shade environment by mobile terminal |
USD946596S1 (en) | 2020-09-30 | 2022-03-22 | Masimo Corporation | Display screen or portion thereof with graphical user interface |
USD946597S1 (en) | 2020-09-30 | 2022-03-22 | Masimo Corporation | Display screen or portion thereof with graphical user interface |
USD946598S1 (en) | 2020-09-30 | 2022-03-22 | Masimo Corporation | Display screen or portion thereof with graphical user interface |
USD997365S1 (en) | 2021-06-24 | 2023-08-29 | Masimo Corporation | Physiological nose sensor |
USD1000975S1 (en) | 2021-09-22 | 2023-10-10 | Masimo Corporation | Wearable temperature measurement device |
Family Cites Families (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3821550A (en) * | 1969-07-18 | 1974-06-28 | Deere & Co | Plant thinner having radiant energy plant detecting means |
US3822098A (en) * | 1973-05-02 | 1974-07-02 | Mc Donnell Douglas Corp | Multispectral sensor means measuring depolarized radiation |
US4306152A (en) * | 1979-07-23 | 1981-12-15 | Anarad, Inc. | Optical fluid analyzer |
DE2934190A1 (en) * | 1979-08-23 | 1981-03-19 | Müller, Gerhard, Prof. Dr.-Ing., 7080 Aalen | METHOD AND DEVICE FOR MOLECULAR SPECTROSCOPY, ESPECIALLY FOR DETERMINING METABOLISM PRODUCTS |
US4655225A (en) * | 1985-04-18 | 1987-04-07 | Kurabo Industries Ltd. | Spectrophotometric method and apparatus for the non-invasive |
US4738535A (en) * | 1986-07-22 | 1988-04-19 | Pacific Scientific Company | Optical instrument employing fiber optics to direct light through tilting filter wheel |
US4805623A (en) * | 1987-09-04 | 1989-02-21 | Vander Corporation | Spectrophotometric method for quantitatively determining the concentration of a dilute component in a light- or other radiation-scattering environment |
JPH0827235B2 (en) * | 1987-11-17 | 1996-03-21 | 倉敷紡績株式会社 | Spectroscopic method for measuring sugar concentration |
US4882492A (en) * | 1988-01-19 | 1989-11-21 | Biotronics Associates, Inc. | Non-invasive near infrared measurement of blood analyte concentrations |
US5086229A (en) * | 1989-01-19 | 1992-02-04 | Futrex, Inc. | Non-invasive measurement of blood glucose |
ATE80225T1 (en) * | 1989-05-23 | 1992-09-15 | Biosensors Technology Inc | METHOD OF DETERMINING SUBSTANCES IN ABSORBING AND SCATTERING MATRIX MATERIALS BY RADIATION ABSORPTION. |
US5023804A (en) * | 1989-05-23 | 1991-06-11 | The Perkin-Elmer Corporation | Method and apparatus for comparing spectra |
US4975581A (en) * | 1989-06-21 | 1990-12-04 | University Of New Mexico | Method of and apparatus for determining the similarity of a biological analyte from a model constructed from known biological fluids |
CA2028261C (en) * | 1989-10-28 | 1995-01-17 | Won Suck Yang | Non-invasive method and apparatus for measuring blood glucose concentration |
AU7302991A (en) * | 1990-02-02 | 1991-08-21 | Boston Advanced Technologies, Inc. | Systems for material analysis based on reflectance ratio detection |
US5054487A (en) * | 1990-02-02 | 1991-10-08 | Boston Advanced Technologies, Inc. | Laser systems for material analysis based on reflectance ratio detection |
US5222496A (en) * | 1990-02-02 | 1993-06-29 | Angiomedics Ii, Inc. | Infrared glucose sensor |
US5222495A (en) * | 1990-02-02 | 1993-06-29 | Angiomedics Ii, Inc. | Non-invasive blood analysis by near infrared absorption measurements using two closely spaced wavelengths |
US5146091A (en) * | 1990-04-19 | 1992-09-08 | Inomet, Inc. | Body fluid constituent measurement utilizing an interference pattern |
GB2248925B (en) * | 1990-09-18 | 1994-08-24 | Anthony Michael Charles Davies | Method and apparatus for calibrating a spectrometer |
US5121337A (en) * | 1990-10-15 | 1992-06-09 | Exxon Research And Engineering Company | Method for correcting spectral data for data due to the spectral measurement process itself and estimating unknown property and/or composition data of a sample using such method |
US5209231A (en) * | 1990-11-02 | 1993-05-11 | University Of Connecticut | Optical glucose sensor apparatus and method |
GB9106672D0 (en) * | 1991-03-28 | 1991-05-15 | Abbey Biosystems Ltd | Method and apparatus for glucose concentration monitoring |
US5242602A (en) * | 1992-03-04 | 1993-09-07 | W. R. Grace & Co.-Conn. | Spectrophotometric monitoring of multiple water treatment performance indicators using chemometrics |
US5370114A (en) * | 1992-03-12 | 1994-12-06 | Wong; Jacob Y. | Non-invasive blood chemistry measurement by stimulated infrared relaxation emission |
DK39792D0 (en) * | 1992-03-25 | 1992-03-25 | Foss Electric As | PROCEDURE FOR DETERMINING A COMPONENT |
US5406082A (en) * | 1992-04-24 | 1995-04-11 | Thiokol Corporation | Surface inspection and characterization system and process |
US5355880A (en) * | 1992-07-06 | 1994-10-18 | Sandia Corporation | Reliable noninvasive measurement of blood gases |
US5360004A (en) * | 1992-12-09 | 1994-11-01 | Diasense, Inc. | Non-invasive determination of analyte concentration using non-continuous radiation |
EP0631137B1 (en) * | 1993-06-25 | 2002-03-20 | Edward W. Stark | Glucose related measurement method and apparatus |
WO1995005120A1 (en) * | 1993-08-12 | 1995-02-23 | Kurashiki Boseki Kabushiki Kaisha | Blood sugar level non-invasion measuring method and measuring instrument therefor |
US5459317A (en) * | 1994-02-14 | 1995-10-17 | Ohio University | Method and apparatus for non-invasive detection of physiological chemicals, particularly glucose |
US5500530A (en) * | 1994-10-31 | 1996-03-19 | Spar Aerospace Limited | Electro-optic ice detection |
SG38866A1 (en) * | 1995-07-31 | 1997-04-17 | Instrumentation Metrics Inc | Liquid correlation spectrometry |
US5747806A (en) * | 1996-02-02 | 1998-05-05 | Instrumentation Metrics, Inc | Method and apparatus for multi-spectral analysis in noninvasive nir spectroscopy |
-
1996
- 1996-02-02 US US08/596,409 patent/US5747806A/en not_active Expired - Fee Related
-
1997
- 1997-01-31 AT AT97904046T patent/ATE239910T1/en not_active IP Right Cessation
- 1997-01-31 PL PL97328060A patent/PL184609B1/en not_active IP Right Cessation
- 1997-01-31 EP EP97904046A patent/EP0877926B1/en not_active Expired - Lifetime
- 1997-01-31 JP JP9527784A patent/JPH11506207A/en not_active Withdrawn
- 1997-01-31 DE DE69721732T patent/DE69721732T2/en not_active Expired - Fee Related
- 1997-01-31 NZ NZ331158A patent/NZ331158A/en unknown
- 1997-01-31 WO PCT/US1997/001370 patent/WO1997028438A1/en not_active Application Discontinuation
- 1997-01-31 CZ CZ982392A patent/CZ239298A3/en unknown
- 1997-01-31 BR BR9707246-0A patent/BR9707246A/en not_active IP Right Cessation
- 1997-01-31 KR KR1019980705965A patent/KR19990082236A/en not_active Application Discontinuation
- 1997-01-31 CN CN97193402A patent/CN1101934C/en not_active Expired - Fee Related
- 1997-01-31 TW TW086101274A patent/TW426802B/en not_active IP Right Cessation
- 1997-01-31 DK DK97904046T patent/DK0877926T3/en active
- 1997-01-31 CA CA002244111A patent/CA2244111C/en not_active Expired - Fee Related
-
1998
- 1998-01-28 US US09/014,933 patent/US5945676A/en not_active Expired - Lifetime
-
1999
- 1999-10-19 HK HK99104604A patent/HK1019635A1/en not_active IP Right Cessation
-
2002
- 2002-02-05 JP JP2002028798A patent/JP2002236097A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
KR19990082236A (en) | 1999-11-25 |
JP2002236097A (en) | 2002-08-23 |
BR9707246A (en) | 2001-10-02 |
WO1997028438A1 (en) | 1997-08-07 |
DK0877926T3 (en) | 2003-09-01 |
US5747806A (en) | 1998-05-05 |
PL328060A1 (en) | 1999-01-04 |
CZ239298A3 (en) | 1999-07-14 |
DE69721732D1 (en) | 2003-06-12 |
CN1214769A (en) | 1999-04-21 |
TW426802B (en) | 2001-03-21 |
NZ331158A (en) | 1999-10-28 |
PL184609B1 (en) | 2002-11-29 |
JPH11506207A (en) | 1999-06-02 |
AU1844997A (en) | 1997-08-22 |
EP0877926A1 (en) | 1998-11-18 |
HK1019635A1 (en) | 2000-02-18 |
AU713502B2 (en) | 1999-12-02 |
US5945676A (en) | 1999-08-31 |
DE69721732T2 (en) | 2004-03-18 |
EP0877926B1 (en) | 2003-05-07 |
CN1101934C (en) | 2003-02-19 |
ATE239910T1 (en) | 2003-05-15 |
CA2244111A1 (en) | 1997-08-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2244111C (en) | Method and apparatus for multi-spectral analysis in noninvasive nir spectroscopy | |
EP0877925B1 (en) | Method and apparatus for multi-spectral analysis in noninvasive infrared spectroscopy | |
WO1997028437A9 (en) | Method and apparatus for multi-spectral analysis in noninvasive infrared spectroscopy | |
US5750994A (en) | Positive correlation filter systems and methods of use thereof | |
US5360004A (en) | Non-invasive determination of analyte concentration using non-continuous radiation | |
US6061582A (en) | Method and apparatus for non-invasive determination of physiological chemicals, particularly glucose | |
WO1996013202A1 (en) | Non-invasive determination of analyte concentration in body of mammals | |
EP0623307A1 (en) | Non-invasive determination of constituent concentration using non-continuous radiation | |
JPH09159606A (en) | Liquid-correlation spectrometry | |
AU713502C (en) | Method and apparatus for multi-spectral analysis in noninvasive NIR spectroscopy | |
JPH11178813A (en) | Method and device for quantitatively determining glucose concentration | |
CA2169881C (en) | Liquid correlation spectrometry | |
WO1996013204A1 (en) | Determination of analyte concentration using non-continuous radiation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
MKLA | Lapsed |