CA2111868A1 - A method for providing general calibration for near infrared instruments for measurement of blood glucose - Google Patents
A method for providing general calibration for near infrared instruments for measurement of blood glucoseInfo
- Publication number
- CA2111868A1 CA2111868A1 CA002111868A CA2111868A CA2111868A1 CA 2111868 A1 CA2111868 A1 CA 2111868A1 CA 002111868 A CA002111868 A CA 002111868A CA 2111868 A CA2111868 A CA 2111868A CA 2111868 A1 CA2111868 A1 CA 2111868A1
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- calibration
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- range
- blood
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Links
- 238000005259 measurement Methods 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims abstract description 48
- 239000008280 blood Substances 0.000 title claims description 64
- 210000004369 blood Anatomy 0.000 title claims description 64
- 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 title claims description 36
- 239000008103 glucose Substances 0.000 title claims description 36
- 238000004458 analytical method Methods 0.000 claims abstract description 28
- 230000003595 spectral effect Effects 0.000 claims abstract description 25
- 230000003287 optical effect Effects 0.000 claims description 24
- 239000012491 analyte Substances 0.000 claims description 18
- 238000010521 absorption reaction Methods 0.000 claims description 10
- 238000001228 spectrum Methods 0.000 abstract description 6
- 238000002329 infrared spectrum Methods 0.000 abstract description 3
- 238000004445 quantitative analysis Methods 0.000 abstract description 2
- 239000000470 constituent Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 6
- 238000013459 approach Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 241000209149 Zea Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 1
- 240000007643 Phytolacca americana Species 0.000 description 1
- 238000004164 analytical calibration Methods 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000004159 blood analysis Methods 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000004060 metabolic process Effects 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
- 238000000611 regression analysis Methods 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
- 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
- A61B5/1495—Calibrating or testing of in-vivo probes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
-
- 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
- G01N21/27—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands using photo-electric detection ; circuits for computing concentration
- G01N21/274—Calibration, base line adjustment, drift correction
-
- 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
- G01N2201/00—Features of devices classified in G01N21/00
- G01N2201/12—Circuits of general importance; Signal processing
- G01N2201/129—Using chemometrical methods
Abstract
A method is disclosed for accurately providing general calibration of near-infrared quantitative analysis instruments for almost any individual user. The general calibration method comprises comparing an individual's near-infrared spectrum to a plurality of near-infrared spectral clusters, (high range, 370), (low range, 170), (very low range, 150). Each near-infrared spectral cluster has a set of calibration constants associated therewith. The calibration constants of the spectral cluster most closely associated with the individual spectra are used to custom calibrate the near-infrared analysis measurement instrument.
Description
W092/22804 2 1 1 ~ 3 PCT/US92/0513~ -A METHOD FOR PROVIDING GENERAL
CALIBR~TION FOR NERR INFRARED
INSTRUMENTS FOR MEASUXEMENT
BACKGROUND OF THE INVENTION
Cross-Reference to Related APPlication This application is a continuation-in-part of copending application Serial No. 07/682,249, filed April 9, 1991, whtch is a continuation-in-part of copending application Serial No. 07/565,302, filed August 10, 1990, which is a continuation-in-part of copending application Serial No. 07/544,580, filed June 27, 1990, which is a continuation-in-part of copending applicati~n Serial No. 07/238,~04, filed Ja~uary 19, 1989.
Field of the Invention This invention relates to instruments and methods for the non-invasive quantitative measurement of blood analytes. More specifically, this invention relates to a method for providi.rg general calibration for neax-infrared instruments for measurement of blood analytes.
Descri~tion of Backqround Art Information concerning the chemical composition of blood is widely used to assess the health characteristic~ of both people and animals. For example, analysis of the glucose content of blood W092/22804 PCT/U~92/05134 provides an indication of the current status of metabolism. Blood analysis, by the detection of above or below normal levels of various substances, also provides a direct indication of the pre~ence of certain types of diseases and dysfunctions.
A current type of blood glucose analytical instrumentation is available for the specific purpose of determining blood glucose levels in people with ~;~
diabetes. This technology u~es a small blood ~ample from a finger poke which is placed on a chemially treated carrier and is inserted into a portable battery operated instrument. The instrument analyzes the blood sample and provides a blood glucose level reading in a ;
short period of time. `~
A different class of blood glucose analytical instruments is the near-infrared quantitative analysis instrument which noninvasively measures blood glucose, such as the type described in copending application `
Serial ~o. 07/565,302. The noninvasive blood glucose measurement instrument analyzes near-infrared energy following interactance with venous or arterial blood, or transmission through a blood-containing body part.
These instruments give accurate blood ~lucose level readings and readily lend themselves to at-home testing by diabetic~.
A limitation of the near-infrared blood glucose ~.neasurement instruments has been that each instrument may be required to be custom calibrated for each individual user. The need for individual custom calibration results from the different combination of water level, fat level and protein level in various individuals which causes variations in energy absorption. Since the amount of glucose in the body is le3s than one thousandth of these other constituents, W092J22804 2 1 1 1 '~ 6 ~ PCT/US92/05134 variations of these constituents which exist among different people has made a general or universal calibration appear unlikely.
The current approach for custom calibrating near-S infrared blood glucose measurement instruments is to use an in-vitro technique that requires removing blood from the sub~ect and having an automatic instrument measure the glucose level of that blood. Such in-vitro measurements are typically made with either the commercially available Biostator or the experimental Kowarski Continuous Monitor. Each of the above instruments requires a catheter to be inserted into the sub~ect and blood withdrawn over a one to two hour period. Although such an approach is feasible, it lS places a significant new burden on the doctor and the medical facility to have enough time, room and equipment to be able to calibrate instruments in this fashion.
In another technique, a low-cost method and means is used for providing custom calibration for n~ar-infrared instruments for measurement of blood glucose which comprises obtaining a plurality of blood samples from an individual at a predetermined time interval and for a predetermined period of time. Blood glucose measurements for each blood sample ~re obtained an~ are entersd into the near-infrared instrument. ~oninva-Qive near-infrared optical absorption measuremen~s are concomitantly taken through a body part of the individual at a second predetermined time interval and are reco~ded in the analysis instrument. Calibrstion regression analysis is then performed utilizing means for linearly interpolating the blood sample glucose measurements with the near-infrared optical mea3urements to custom calibrate the near-infrared i~lll~b~
w092~22804 PCT/US92/05134 instrument for the individual. Although representing a significant advancement in custom calibration, this technique does not permit virtually any user to obtain accurate blood glucose level measurements without first 5 having to individually calibrate the instrument. As a result, individual custom calibration can be a significant burden on time and on medical facilities.
Thus, there is a great need for a technique which allows an individual user to obtain f~st and accurate blood glucose leYel measurements without having to first individually calibrate the analysis instrument.
SUMMARY OF THE INVENTION
In accordance with the present invention, a method of calibration is disclo~ed for calibrating a near-lS infrared instrument for the measurement of a ~lood analyte to accommodate almost any individual user. The calibration method according to the present invention comprises ohtaining a near-infrared optical measurement from an individual and comparing the optical measurement with a plurality of spectral data clusters.
Each spectral data cluster has associated therewith a set of calibration constants for calibrating the analysis instrument for the individual. The individual's optical measurement data is compared to the plurality of spectral data clusters to determine which clu3ter the data most closely identifies with.
The calibration constants associated with that cluster are then used to calibrate the near-infrared snalysis instrument for that individual. This calibration method is a significant advancement in near-infrared analysis instrument calibration because accurate calibration can be accomplished for any given w092/2~8~ 2 1 1 1 8 ~ ~ PCT/US92/osl~ ~
individual without having to go through the custom calibration techniques of the prior art.
- In another aspect of the present invention, a multiple calibration method is used to provide additional accuracy in blood analyte measurements. The multiple calibration method involves applying a near-infrared optical measurement to a first calibration which calibrates the optical measurement over substantially the entire range of possible blood analyte concentrations and produces a first calibrated value. Further, the first calibration determines whether the first calibrated value falls into a first higher range or a first lower range of possible blood analyte concentrations. A higher range calibration is selected for the first higher range and which calibratss the first calibrated value over the higher range. A lower range calibration is also selected for the first lower range and calibrates the first calibrated signal over the ~ower range. Based on which range the first calibrated value falls within, an appropriate second calibration is applied to pro~ide a highly accurate measurement of blood analyte concentration.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a flow diagram illustrating the method for calibrating a near-infrared analysis instrument for the measurem~nt of blood glucose levels according to one embodiment of the present invention;
Figures 2A-C are graphs illustrating spectra - 30 clusters according to the present invention;
Figure 3 is a front schematic view of a noninvasive near-infrared analysis instrument which can 2111~
w092/22804 PCT/US92/05134 be generally calibrated according to the method of the present invention;
Figure 4 is a flow diagram illustrating the method for calibrating a near-infrared analysis instrument for the measurement of blood glucose levels according to a second aspect of the present invention; and Figures 5 and 6 are block diagrams illustrating the method for calibrating a near-infrared analysis instrument.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is directed toward a method for generally calibrating a noninvasive near-infrared blood glucose measurement instrument. An example of such a near-infrared blood glucose instrument is illustrated in copending application Serial No.
0~/565,302, incorporated herein by reference.
In conventional near-infrared analysis, the analysis instrument must be custom calibrsted for each individual user. Individual custom calibration is a time consuming procedure often xequiring invasive blood samples and resulting in a burden on health care facilities. Custom calibration for the individual user was generally thought to be required because different combinations of water level; fat level and protein level in various individuals cause variation.s in energy absorption.
Figure l illustrates a calibration method according to the present invention which alleviates the need to provide custom calibration for each individual user by utilizing a technique which automatically calibrates the analysis instrument for virtually any individual user. Thus, the general calibration m~thod allows virtually any individual to obtain almost W O 92/22804 2 1 1 1 8 6 8 P(~r/US92/05134 immediate, accurate blood analyte concentration measurements, without prior custom calibration.
The general calibration method accor~ing to the present invention is based upon a discovery that the shapes of the near-infrared spectral data distribution for all individuals, between about approximately 600 and approximately 1,000 nanometers, can be sùbdivided and categorized into a plurality of different ~clusters" or "shapes." The concept of clusters is to subdivide a set of samples that have different characteristics into sets havinq similar characteristics. Cluster theory allows separating samples into distinct separate groups (i.e. clusters), thereby allowing each group to be identified by the type of constituent obtained. In blood glucose analysis, the spectral data distribution is subdivided into approximately six different clusters.
A set of calibration constants associated with each cluster is calculated and stored in the near-infrared analysis instrument.
General calibration for any indi~idual user isaccomplished by obtaining a near-infrared optical measurement spectrum, through a body part, and by comparing the optical measurement spectrum to each of the prestored spectral clusters. The general calibration method of the present invention utilizes means for identifying and assigning a particular cluster from among the six clusters that most closely matches the individual near-infrared optical measurements. Thus, any near-infrared spectra from any - individual user can be assigned or matched to a specific cluster.
- The calibration constants associated with the cluster identified as being mo~t closely corresponding o~ ~ PCT/US~2~05134 to the measured individual spectrum are then used to calibrate the analysis instrument. Accurate blood glucose level measurements are thereby obtained without havin~ to custom calibrate the analysis for the individual user.
Grouping the individual samples into clusters can be accomplished in any suitable manner. In one approach, all sample spectral curves are visually observed, and representative curves that have certain significant differences from each other are identified and grouped into clusters. Figures 2A-C show curves which illustrate these clusters. As shown therein, the vertical axis is Log l/T (optical density value), and the horizontal axis is wavelength which varies between 600 nanometers to l000 nanometers. The vertical lines ;
represent the specific optical filters that are installed in the analysis instrument to produce a desired wavelength. These Figures illustrate examples of clusters uniquely identified from large quantities of near-infrared spectral ~urve samplcs.
Once the clusters have been identified, assignment of the individual spectral data measurements thereto can be accomplished in any suitable way. In one embodiment, the optical measurement data is stati~tically compared with the cluster data.
Specifi~ally, this is done by calculating the square of the correlation coefficient ~"R2") between the measurement curve data, from the body part bein~
measured, and the "master scan" or prestored distribution curve for each cluster. The cluster with the highest R2 value to that individual m0asurement, i.e. typically a finger mea~urement, would be the appropriate cluster for application of calibration constants. A correlation of approximately 0.90 or W092/22~04 2 1 1 1 8 6 ~ PCT/US92/051~
higher results in accurate calibration. The blood glucose level for that individual would then be calculated using the calibration constants for that cluster.
Another method for identifying and assigning a particular near-infrared spectral cluster to the individual measured spectrum involves usin~ general statistical analysis software, such as SAS
(~tatistical Analysis Systems") made by SAS
Instruments, Inc., Cary, North Carolina. The SAS
analysis provides fast and accurate determination of the spectral clusters, and which cluster the individual's measured spectral data most closely fits.
A near-infrared noninvasive blood glucose measurement instrument which can be generally calibrated employing the method of the pre~ent invention is illustrated schematically in Figure 3.
Noninvasive glucose meter 1 is designed to measure blood glucose levels through the distal portion of the test subject's fin~er. The analytical in3trument contains at least one near-infrared energy ~ource for introducing near-infrared energy into a test subject's finger. Near-infrared point sources 5 and 6 are shown for illustrative purposes in Figure 3. The analytical instrument also utilizes detector 8 for detecting near-infrared energy emerging from the test subjec~'s body part. Detector 8 is electrically connected ~o signal processing means 10 which, according to its programming, procasses the signal produced by the detector 8 into a signal indicative of the quantity of - qlucose present in the blood of the test sub~ect.
Amplifier 9 amplifies the signal produced by the detector 8 before it is received into the processing means 10. Input/output connector 25 is electrically W092/22~04 PCT/US~2/05134 connected to the processing means l0 and allows the analytical instrument to be connected to a "host"
instrument such as a computer. Input/output connector 25 enables the spectral clusters to be entered into the analysis instrument and stored in storage means 20~
such as an electrically erasable programable read only memory (EEPROM). The noninvasive glucose meter l operates substantially as disclosed in application Serial No. 07/565,302, incorporated herein by reference.
The general calibration method of the present invention is based upon the discovery that almost all individuals, independent of race, ethnic origin, medications, nail polish, and other parameters which distinguish one individual's near-infrared absorption measurements from another individual'~ measuremsnt~, can be categsrized into approximately six different near-infrared spectral clusters. By comparing the test sub~ect's individual near-infrared spectrum distribution to the spectral distribution curve of each different cluster, and using the calibration constants associated with the most closely matching cluster, accurate, general calibration can be accomplished for almo~t any individual.
Figure 4 illustrates a multiple calibration method according to another aspect of the present invention.
The multiple calibration method effectively compensates for inaccuracies caused by large variations in measured constituent values. For example, in the blood glucose application there is typically a factor of twelve to one change in constituent value (i.e. 40 to 500 mg/dl~.
Stated differently, individual blood glucose concentrations can range anywhere from 40 to 500 mg~dl~
Standard calibration approaches are linear techniques W092/228~ 2 1 1 1 ~ fi ~ PCT/US92/051~
and are therefore normally limited to applications that have relati~ely small changes in a constituent value.
Thus, large ranges in blood glucose constituent values are less amenable to linear analysis and can result in S inaccurate calibration.
A similar problem exists in many agricultural applications. For example, the moisture level of corn, at the time of harvest, can be as high as 48%.
However, after the corn is allowed to dry, the moisture level could be as low as 8~--a six to one variation of the constituent desired to be measured. The technique used in the agricultural application is to subdivide the calibration into two different ranges:
~ Low Ranqe- Calibration from 8% to 30%, and - 15 ~ Hiqh Ranqe- Calibration from 26% to 48%.
An individual operator -~elects either the low range calibration or the high range calibration. In using the above concept, the six to one range change is r~duced to two ranges, with the maximum ratio of 3.8 to 1. These smaller ranges are more amenable to linear analysis, thereby, allowing accurate calibration.
Figures 5 and 6 illustrate the multiple calibration concept applied to blood glucose analysis.
An important advancement is that the present invention utilizes an initial calibration measurement which is provided to perform a calibration over the entire range of near-infrared data. The purpose of the initial calibration measurement is to decide which of the two - alternate calibrations will be used--either the hiqh range calibration or the lower range calibration.
As illustrated in Figure 5, the initial calibration range is between 40 and 500 mg/dl. It is 2 ~ PCT/US92/05134 assumed that the initial calibration by the initial calibration measurement has a two sigma value (standard error of estimate) of l00 mg/dl. Thus, the high range extends up from l00 mg/dl below the midpoint of 270.
Likewise, the low range extends downward from l00 mg/dl above the midpoint of 270. ;-Operation of the multiple calibration method will be described hereinafter. A person places her finger in the near-infrared blood glucose analysis instrument to obtain a near-infrared optical absorption measurement. The optical mea~urement i~ calibrated over substantially the entire range of possible blood . analyte concentrations. This initial calibration will provide a first calibrated value, which is not displayed, that allows the instrument to select either -~
the higher range or the lower range calibration. If it picks the high range calibration, the value obtained therefrom will be displayed. However, if it selects the low range calibration, and the result is less than approximately l50 mg/dl, then the instrument u~es a more precise calibration for the range between approximately 40 and approximately 150 mg/dl.
Figure 6 illustrates a similar example where the range i8 re3tsicted to between 40 and 400 mg/dl.
Since a microproce~sor utilized in the instrument is able to perform these types of calculations in milliseconds, the user never knows that these alternate calibrations are being selected. The actual glucose measurement value in displayed is a fraction of a second.
The multiple calibration method according to the pre~ent invention can be used to increase the accuracy of an individually custom calibrated near-infrared ~092/22~ 2 1 1 1 8 6 8 PCT/US92/~1~
analysis instrument or an instrument utilizing the general calibration method as disclosed above.
~ The multiple calibration method provides greater calibration accuracy used by itself or in combination with another calibration technique.
Although the invention has been de~cribed in connection with certain preferred embodiments, it is not limited to them. Modifications within the scope of the following claims will be apparent to those skilled in the art.
_ _ , _ _ .. ... . .... . .. . .. ... . . . . .. . . .. .. . . . . . . . . .. .... . . . . .. . . .
CALIBR~TION FOR NERR INFRARED
INSTRUMENTS FOR MEASUXEMENT
BACKGROUND OF THE INVENTION
Cross-Reference to Related APPlication This application is a continuation-in-part of copending application Serial No. 07/682,249, filed April 9, 1991, whtch is a continuation-in-part of copending application Serial No. 07/565,302, filed August 10, 1990, which is a continuation-in-part of copending application Serial No. 07/544,580, filed June 27, 1990, which is a continuation-in-part of copending applicati~n Serial No. 07/238,~04, filed Ja~uary 19, 1989.
Field of the Invention This invention relates to instruments and methods for the non-invasive quantitative measurement of blood analytes. More specifically, this invention relates to a method for providi.rg general calibration for neax-infrared instruments for measurement of blood analytes.
Descri~tion of Backqround Art Information concerning the chemical composition of blood is widely used to assess the health characteristic~ of both people and animals. For example, analysis of the glucose content of blood W092/22804 PCT/U~92/05134 provides an indication of the current status of metabolism. Blood analysis, by the detection of above or below normal levels of various substances, also provides a direct indication of the pre~ence of certain types of diseases and dysfunctions.
A current type of blood glucose analytical instrumentation is available for the specific purpose of determining blood glucose levels in people with ~;~
diabetes. This technology u~es a small blood ~ample from a finger poke which is placed on a chemially treated carrier and is inserted into a portable battery operated instrument. The instrument analyzes the blood sample and provides a blood glucose level reading in a ;
short period of time. `~
A different class of blood glucose analytical instruments is the near-infrared quantitative analysis instrument which noninvasively measures blood glucose, such as the type described in copending application `
Serial ~o. 07/565,302. The noninvasive blood glucose measurement instrument analyzes near-infrared energy following interactance with venous or arterial blood, or transmission through a blood-containing body part.
These instruments give accurate blood ~lucose level readings and readily lend themselves to at-home testing by diabetic~.
A limitation of the near-infrared blood glucose ~.neasurement instruments has been that each instrument may be required to be custom calibrated for each individual user. The need for individual custom calibration results from the different combination of water level, fat level and protein level in various individuals which causes variations in energy absorption. Since the amount of glucose in the body is le3s than one thousandth of these other constituents, W092J22804 2 1 1 1 '~ 6 ~ PCT/US92/05134 variations of these constituents which exist among different people has made a general or universal calibration appear unlikely.
The current approach for custom calibrating near-S infrared blood glucose measurement instruments is to use an in-vitro technique that requires removing blood from the sub~ect and having an automatic instrument measure the glucose level of that blood. Such in-vitro measurements are typically made with either the commercially available Biostator or the experimental Kowarski Continuous Monitor. Each of the above instruments requires a catheter to be inserted into the sub~ect and blood withdrawn over a one to two hour period. Although such an approach is feasible, it lS places a significant new burden on the doctor and the medical facility to have enough time, room and equipment to be able to calibrate instruments in this fashion.
In another technique, a low-cost method and means is used for providing custom calibration for n~ar-infrared instruments for measurement of blood glucose which comprises obtaining a plurality of blood samples from an individual at a predetermined time interval and for a predetermined period of time. Blood glucose measurements for each blood sample ~re obtained an~ are entersd into the near-infrared instrument. ~oninva-Qive near-infrared optical absorption measuremen~s are concomitantly taken through a body part of the individual at a second predetermined time interval and are reco~ded in the analysis instrument. Calibrstion regression analysis is then performed utilizing means for linearly interpolating the blood sample glucose measurements with the near-infrared optical mea3urements to custom calibrate the near-infrared i~lll~b~
w092~22804 PCT/US92/05134 instrument for the individual. Although representing a significant advancement in custom calibration, this technique does not permit virtually any user to obtain accurate blood glucose level measurements without first 5 having to individually calibrate the instrument. As a result, individual custom calibration can be a significant burden on time and on medical facilities.
Thus, there is a great need for a technique which allows an individual user to obtain f~st and accurate blood glucose leYel measurements without having to first individually calibrate the analysis instrument.
SUMMARY OF THE INVENTION
In accordance with the present invention, a method of calibration is disclo~ed for calibrating a near-lS infrared instrument for the measurement of a ~lood analyte to accommodate almost any individual user. The calibration method according to the present invention comprises ohtaining a near-infrared optical measurement from an individual and comparing the optical measurement with a plurality of spectral data clusters.
Each spectral data cluster has associated therewith a set of calibration constants for calibrating the analysis instrument for the individual. The individual's optical measurement data is compared to the plurality of spectral data clusters to determine which clu3ter the data most closely identifies with.
The calibration constants associated with that cluster are then used to calibrate the near-infrared snalysis instrument for that individual. This calibration method is a significant advancement in near-infrared analysis instrument calibration because accurate calibration can be accomplished for any given w092/2~8~ 2 1 1 1 8 ~ ~ PCT/US92/osl~ ~
individual without having to go through the custom calibration techniques of the prior art.
- In another aspect of the present invention, a multiple calibration method is used to provide additional accuracy in blood analyte measurements. The multiple calibration method involves applying a near-infrared optical measurement to a first calibration which calibrates the optical measurement over substantially the entire range of possible blood analyte concentrations and produces a first calibrated value. Further, the first calibration determines whether the first calibrated value falls into a first higher range or a first lower range of possible blood analyte concentrations. A higher range calibration is selected for the first higher range and which calibratss the first calibrated value over the higher range. A lower range calibration is also selected for the first lower range and calibrates the first calibrated signal over the ~ower range. Based on which range the first calibrated value falls within, an appropriate second calibration is applied to pro~ide a highly accurate measurement of blood analyte concentration.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a flow diagram illustrating the method for calibrating a near-infrared analysis instrument for the measurem~nt of blood glucose levels according to one embodiment of the present invention;
Figures 2A-C are graphs illustrating spectra - 30 clusters according to the present invention;
Figure 3 is a front schematic view of a noninvasive near-infrared analysis instrument which can 2111~
w092/22804 PCT/US92/05134 be generally calibrated according to the method of the present invention;
Figure 4 is a flow diagram illustrating the method for calibrating a near-infrared analysis instrument for the measurement of blood glucose levels according to a second aspect of the present invention; and Figures 5 and 6 are block diagrams illustrating the method for calibrating a near-infrared analysis instrument.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is directed toward a method for generally calibrating a noninvasive near-infrared blood glucose measurement instrument. An example of such a near-infrared blood glucose instrument is illustrated in copending application Serial No.
0~/565,302, incorporated herein by reference.
In conventional near-infrared analysis, the analysis instrument must be custom calibrsted for each individual user. Individual custom calibration is a time consuming procedure often xequiring invasive blood samples and resulting in a burden on health care facilities. Custom calibration for the individual user was generally thought to be required because different combinations of water level; fat level and protein level in various individuals cause variation.s in energy absorption.
Figure l illustrates a calibration method according to the present invention which alleviates the need to provide custom calibration for each individual user by utilizing a technique which automatically calibrates the analysis instrument for virtually any individual user. Thus, the general calibration m~thod allows virtually any individual to obtain almost W O 92/22804 2 1 1 1 8 6 8 P(~r/US92/05134 immediate, accurate blood analyte concentration measurements, without prior custom calibration.
The general calibration method accor~ing to the present invention is based upon a discovery that the shapes of the near-infrared spectral data distribution for all individuals, between about approximately 600 and approximately 1,000 nanometers, can be sùbdivided and categorized into a plurality of different ~clusters" or "shapes." The concept of clusters is to subdivide a set of samples that have different characteristics into sets havinq similar characteristics. Cluster theory allows separating samples into distinct separate groups (i.e. clusters), thereby allowing each group to be identified by the type of constituent obtained. In blood glucose analysis, the spectral data distribution is subdivided into approximately six different clusters.
A set of calibration constants associated with each cluster is calculated and stored in the near-infrared analysis instrument.
General calibration for any indi~idual user isaccomplished by obtaining a near-infrared optical measurement spectrum, through a body part, and by comparing the optical measurement spectrum to each of the prestored spectral clusters. The general calibration method of the present invention utilizes means for identifying and assigning a particular cluster from among the six clusters that most closely matches the individual near-infrared optical measurements. Thus, any near-infrared spectra from any - individual user can be assigned or matched to a specific cluster.
- The calibration constants associated with the cluster identified as being mo~t closely corresponding o~ ~ PCT/US~2~05134 to the measured individual spectrum are then used to calibrate the analysis instrument. Accurate blood glucose level measurements are thereby obtained without havin~ to custom calibrate the analysis for the individual user.
Grouping the individual samples into clusters can be accomplished in any suitable manner. In one approach, all sample spectral curves are visually observed, and representative curves that have certain significant differences from each other are identified and grouped into clusters. Figures 2A-C show curves which illustrate these clusters. As shown therein, the vertical axis is Log l/T (optical density value), and the horizontal axis is wavelength which varies between 600 nanometers to l000 nanometers. The vertical lines ;
represent the specific optical filters that are installed in the analysis instrument to produce a desired wavelength. These Figures illustrate examples of clusters uniquely identified from large quantities of near-infrared spectral ~urve samplcs.
Once the clusters have been identified, assignment of the individual spectral data measurements thereto can be accomplished in any suitable way. In one embodiment, the optical measurement data is stati~tically compared with the cluster data.
Specifi~ally, this is done by calculating the square of the correlation coefficient ~"R2") between the measurement curve data, from the body part bein~
measured, and the "master scan" or prestored distribution curve for each cluster. The cluster with the highest R2 value to that individual m0asurement, i.e. typically a finger mea~urement, would be the appropriate cluster for application of calibration constants. A correlation of approximately 0.90 or W092/22~04 2 1 1 1 8 6 ~ PCT/US92/051~
higher results in accurate calibration. The blood glucose level for that individual would then be calculated using the calibration constants for that cluster.
Another method for identifying and assigning a particular near-infrared spectral cluster to the individual measured spectrum involves usin~ general statistical analysis software, such as SAS
(~tatistical Analysis Systems") made by SAS
Instruments, Inc., Cary, North Carolina. The SAS
analysis provides fast and accurate determination of the spectral clusters, and which cluster the individual's measured spectral data most closely fits.
A near-infrared noninvasive blood glucose measurement instrument which can be generally calibrated employing the method of the pre~ent invention is illustrated schematically in Figure 3.
Noninvasive glucose meter 1 is designed to measure blood glucose levels through the distal portion of the test subject's fin~er. The analytical in3trument contains at least one near-infrared energy ~ource for introducing near-infrared energy into a test subject's finger. Near-infrared point sources 5 and 6 are shown for illustrative purposes in Figure 3. The analytical instrument also utilizes detector 8 for detecting near-infrared energy emerging from the test subjec~'s body part. Detector 8 is electrically connected ~o signal processing means 10 which, according to its programming, procasses the signal produced by the detector 8 into a signal indicative of the quantity of - qlucose present in the blood of the test sub~ect.
Amplifier 9 amplifies the signal produced by the detector 8 before it is received into the processing means 10. Input/output connector 25 is electrically W092/22~04 PCT/US~2/05134 connected to the processing means l0 and allows the analytical instrument to be connected to a "host"
instrument such as a computer. Input/output connector 25 enables the spectral clusters to be entered into the analysis instrument and stored in storage means 20~
such as an electrically erasable programable read only memory (EEPROM). The noninvasive glucose meter l operates substantially as disclosed in application Serial No. 07/565,302, incorporated herein by reference.
The general calibration method of the present invention is based upon the discovery that almost all individuals, independent of race, ethnic origin, medications, nail polish, and other parameters which distinguish one individual's near-infrared absorption measurements from another individual'~ measuremsnt~, can be categsrized into approximately six different near-infrared spectral clusters. By comparing the test sub~ect's individual near-infrared spectrum distribution to the spectral distribution curve of each different cluster, and using the calibration constants associated with the most closely matching cluster, accurate, general calibration can be accomplished for almo~t any individual.
Figure 4 illustrates a multiple calibration method according to another aspect of the present invention.
The multiple calibration method effectively compensates for inaccuracies caused by large variations in measured constituent values. For example, in the blood glucose application there is typically a factor of twelve to one change in constituent value (i.e. 40 to 500 mg/dl~.
Stated differently, individual blood glucose concentrations can range anywhere from 40 to 500 mg~dl~
Standard calibration approaches are linear techniques W092/228~ 2 1 1 1 ~ fi ~ PCT/US92/051~
and are therefore normally limited to applications that have relati~ely small changes in a constituent value.
Thus, large ranges in blood glucose constituent values are less amenable to linear analysis and can result in S inaccurate calibration.
A similar problem exists in many agricultural applications. For example, the moisture level of corn, at the time of harvest, can be as high as 48%.
However, after the corn is allowed to dry, the moisture level could be as low as 8~--a six to one variation of the constituent desired to be measured. The technique used in the agricultural application is to subdivide the calibration into two different ranges:
~ Low Ranqe- Calibration from 8% to 30%, and - 15 ~ Hiqh Ranqe- Calibration from 26% to 48%.
An individual operator -~elects either the low range calibration or the high range calibration. In using the above concept, the six to one range change is r~duced to two ranges, with the maximum ratio of 3.8 to 1. These smaller ranges are more amenable to linear analysis, thereby, allowing accurate calibration.
Figures 5 and 6 illustrate the multiple calibration concept applied to blood glucose analysis.
An important advancement is that the present invention utilizes an initial calibration measurement which is provided to perform a calibration over the entire range of near-infrared data. The purpose of the initial calibration measurement is to decide which of the two - alternate calibrations will be used--either the hiqh range calibration or the lower range calibration.
As illustrated in Figure 5, the initial calibration range is between 40 and 500 mg/dl. It is 2 ~ PCT/US92/05134 assumed that the initial calibration by the initial calibration measurement has a two sigma value (standard error of estimate) of l00 mg/dl. Thus, the high range extends up from l00 mg/dl below the midpoint of 270.
Likewise, the low range extends downward from l00 mg/dl above the midpoint of 270. ;-Operation of the multiple calibration method will be described hereinafter. A person places her finger in the near-infrared blood glucose analysis instrument to obtain a near-infrared optical absorption measurement. The optical mea~urement i~ calibrated over substantially the entire range of possible blood . analyte concentrations. This initial calibration will provide a first calibrated value, which is not displayed, that allows the instrument to select either -~
the higher range or the lower range calibration. If it picks the high range calibration, the value obtained therefrom will be displayed. However, if it selects the low range calibration, and the result is less than approximately l50 mg/dl, then the instrument u~es a more precise calibration for the range between approximately 40 and approximately 150 mg/dl.
Figure 6 illustrates a similar example where the range i8 re3tsicted to between 40 and 400 mg/dl.
Since a microproce~sor utilized in the instrument is able to perform these types of calculations in milliseconds, the user never knows that these alternate calibrations are being selected. The actual glucose measurement value in displayed is a fraction of a second.
The multiple calibration method according to the pre~ent invention can be used to increase the accuracy of an individually custom calibrated near-infrared ~092/22~ 2 1 1 1 8 6 8 PCT/US92/~1~
analysis instrument or an instrument utilizing the general calibration method as disclosed above.
~ The multiple calibration method provides greater calibration accuracy used by itself or in combination with another calibration technique.
Although the invention has been de~cribed in connection with certain preferred embodiments, it is not limited to them. Modifications within the scope of the following claims will be apparent to those skilled in the art.
_ _ , _ _ .. ... . .... . .. . .. ... . . . . .. . . .. .. . . . . . . . . .. .... . . . . .. . . .
Claims (7)
1. A method for calibrating a near-infrared analysis instrument for the measurement of a blood analyte, said method comprising:
(a) obtaining a near-infrared optical absorption measurement through a body part of an individual;
(b) comparing said optical absorption measurement with each spectral cluster of a plurality of spectral clusters, each of said spectral clusters having a set of calibration constants associated therewith;
(c) identifying which of said plurality of spectral clusters corresponds to said optical absorption measurement; and (d) applying the set of calibration constants associated with the identified spectral cluster to said near-infrared optical absorption measurements to obtain a measurement of said blood analyte.
(a) obtaining a near-infrared optical absorption measurement through a body part of an individual;
(b) comparing said optical absorption measurement with each spectral cluster of a plurality of spectral clusters, each of said spectral clusters having a set of calibration constants associated therewith;
(c) identifying which of said plurality of spectral clusters corresponds to said optical absorption measurement; and (d) applying the set of calibration constants associated with the identified spectral cluster to said near-infrared optical absorption measurements to obtain a measurement of said blood analyte.
2. The method as set forth in claim 1, wherein said near-infrared optical measurement is made using energy of between about 600 to about 1000 nanometers.
3. The method as set forth in claim 1, wherein said plurality of spectral cluster is approximately six spectral clusters.
4. The method as set forth in claim 1, wherein said blood analyte is blood glucose levels.
5. A method for accurately calibrating a near-infrared analysis instrument for the measurement of a blood analyte, said method comprising;
(a) obtaining an near-infrared optical absorption measurement in a body part of an individual, wherein said near-infrared optical measurement is made using energy of about 600 to about 1000 nanometers;
(b) applying said optical measurement to an initial calibration means for calibrating said optical measurement over substantially the entire range of possible blood analyte concentrations and determining a first calibrated value;
(c) determining whether said first calibrated value falls into at least a first higher range of possible blood analyte concentrations or a first lower range of possible blood analyte concentrations, said first higher range and said first lower range comprises substantially non-overlapping portions of said entire range of possible blood analyte concentrations, said first higher range and said first lower range each comprising a second calibration means corresponding thereto;
(d) applying to said first calibrated value said second calibration means corresponding to said first higher range or said first lower range based on the determination whether said first calibrated value falls within said first higher range or said first lower range, and producing a second calibrated value representing the measurement of said blood analyte.
(a) obtaining an near-infrared optical absorption measurement in a body part of an individual, wherein said near-infrared optical measurement is made using energy of about 600 to about 1000 nanometers;
(b) applying said optical measurement to an initial calibration means for calibrating said optical measurement over substantially the entire range of possible blood analyte concentrations and determining a first calibrated value;
(c) determining whether said first calibrated value falls into at least a first higher range of possible blood analyte concentrations or a first lower range of possible blood analyte concentrations, said first higher range and said first lower range comprises substantially non-overlapping portions of said entire range of possible blood analyte concentrations, said first higher range and said first lower range each comprising a second calibration means corresponding thereto;
(d) applying to said first calibrated value said second calibration means corresponding to said first higher range or said first lower range based on the determination whether said first calibrated value falls within said first higher range or said first lower range, and producing a second calibrated value representing the measurement of said blood analyte.
6. The method as set forth in claim 5, further comprising applying a third calibration means to said second calibrated value if said second calibrated value falls within a second lower range of blood analyte concentrations, producing a third calibrated value representing the measurement of said blood concentrations.
7. The method as set forth in claim 5, wherein said blood analyte is blood glucose levels.
Applications Claiming Priority (2)
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|---|---|---|---|
| US717,198 | 1991-06-18 | ||
| US07/717,198 US5204532A (en) | 1989-01-19 | 1991-06-18 | Method for providing general calibration for near infrared instruments for measurement of blood glucose |
Publications (1)
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|---|---|
| CA2111868A1 true CA2111868A1 (en) | 1992-12-23 |
Family
ID=24881098
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002111868A Abandoned CA2111868A1 (en) | 1991-06-18 | 1992-06-17 | A method for providing general calibration for near infrared instruments for measurement of blood glucose |
Country Status (7)
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|---|---|
| US (2) | US5204532A (en) |
| EP (1) | EP0590077A4 (en) |
| JP (1) | JPH06508440A (en) |
| AU (1) | AU2251292A (en) |
| CA (1) | CA2111868A1 (en) |
| MX (1) | MX9202953A (en) |
| WO (1) | WO1992022804A1 (en) |
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1992
- 1992-06-17 MX MX9202953A patent/MX9202953A/en not_active IP Right Cessation
- 1992-06-17 AU AU22512/92A patent/AU2251292A/en not_active Abandoned
- 1992-06-17 JP JP5501106A patent/JPH06508440A/en active Pending
- 1992-06-17 CA CA002111868A patent/CA2111868A1/en not_active Abandoned
- 1992-06-17 WO PCT/US1992/005134 patent/WO1992022804A1/en not_active Application Discontinuation
- 1992-06-17 EP EP19920914580 patent/EP0590077A4/en not_active Withdrawn
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1993
- 1993-01-22 US US08/007,967 patent/US5576544A/en not_active Expired - Lifetime
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| EP0590077A1 (en) | 1994-04-06 |
| EP0590077A4 (en) | 1994-10-26 |
| AU2251292A (en) | 1993-01-12 |
| WO1992022804A1 (en) | 1992-12-23 |
| MX9202953A (en) | 1993-02-01 |
| US5576544A (en) | 1996-11-19 |
| US5204532A (en) | 1993-04-20 |
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