Source: http://www.google.com/patents/US6917038?dq=6948823
Timestamp: 2014-10-22 05:05:08
Document Index: 480674773

Matched Legal Cases: ['Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60']

Patent US6917038 - Method and apparatus for adjusting signal variation of an electronically ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsAn analyte detection system non-invasively determines the concentration of an analyte in a sample generating a sample infrared signal indicative of the concentration of the analyte in the sample. The detection system includes a window assembly for receiving the sample infrared signal. The window assembly...http://www.google.com/patents/US6917038?utm_source=gb-gplus-sharePatent US6917038 - Method and apparatus for adjusting signal variation of an electronically controlled infrared transmissive windowAdvanced Patent SearchPublication numberUS6917038 B2Publication typeGrantApplication numberUS 10/302,030Publication dateJul 12, 2005Filing dateNov 21, 2002Priority dateNov 21, 2001Fee statusLapsedAlso published asUS20030146385, WO2003045234A2Publication number10302030, 302030, US 6917038 B2, US 6917038B2, US-B2-6917038, US6917038 B2, US6917038B2InventorsPeng Zheng, Jennifer H. Gable, W. Dale Hall, Kenneth G. Witte, James R. BraigOriginal AssigneeOptiscan Biomedical CorporationExport CitationBiBTeX, EndNote, RefManPatent Citations (19), Non-Patent Citations (1), Referenced by (7), Classifications (9), Legal Events (8) External Links: USPTO, USPTO Assignment, EspacenetMethod and apparatus for adjusting signal variation of an electronically controlled infrared transmissive windowUS 6917038 B2Abstract An analyte detection system non-invasively determines the concentration of an analyte in a sample generating a sample infrared signal indicative of the concentration of the analyte in the sample. The detection system includes a window assembly for receiving the sample infrared signal. The window assembly is adapted to allow the sample infrared signal to transmit therethrough, and generates a window infrared signal. The detection system further includes at least one detector configured to receive both the window infrared signal and the sample infrared signal transmitted through the window assembly. The detector is further adapted to generate a detector signal in response thereto. The detection system further includes a correction module configured to generate a corrected detector signal indicative of the concentration of the analyte in the sample.
1. An analyte detection system for non-invasively determining the concentration of an analyte in a sample, the sample generating a sample infrared signal indicative of the concentration of the analyte in the sample, the detection system comprising:
a window assembly for receiving the sample infrared signal, the window assembly adapted to allow the sample infrared signal to transmit therethrough, the window assembly generating a window infrared signal; at least one detector configured to receive both the window infrared signal and the sample infrared signal transmitted through the window assembly, the detector further adapted to generate a detector signal in response thereto; and a correction module configured to generate a corrected detector signal indicative of the concentration of the analyte in the sample. 2. An analyte detection system for non-invasively determining the concentration of an analyte in a sample, the sample generating a sample infrared signal indicative of the concentration of the analyte in the sample, the detection system comprising:
a window assembly for receiving the sample infrared signal, the window assembly adapted to allow the sample infrared signal to transmit therethrough, the window assembly generating a window infrared signal; at least one detector configured to receive both the window infrared signal and the sample infrared signal transmitted through the window assembly, the detector further adapted to generate a detector signal in response thereto; and a correction module configured to generate a corrected detector signal indicative of the concentration of the analyte in the sample, wherein the correction module generates a correction signal indicative of the window infrared signal, and the correction module generates the corrected detector signal in response to both the correction signal and the detector signal. 3. The analyte detection system of claim 2, additionally comprising at least one resistance temperature device coupled to the window assembly.
4. The analyte detection system of claim 2, wherein the window assembly comprises a heater and at least one monitor.
5. The analyte detection system of claim 4, wherein the monitor comprises an ammeter.
6. The analyte detection system of claim 4, wherein the monitor comprises a voltmeter configured to measure a voltage across the heater.
7. The analyte detection system of claim 4, wherein the monitor comprises a resistance monitor configured to measure a resistance of the heater.
8. The analyte detection system of claim 2, additionally comprising at least one reference detector channel configured to generate the correction signal in response to infrared radiation from the window assembly.
9. A method for improving the sensitivity of a noninvasive infrared analyte detection system having a window assembly and a plurality of detector channels, each detector channel generating a detector signal in response to infrared emissions from a sample and infrared emissions from the window assembly, the method comprising:
measuring a window signal for each detector channel, each window signal having a corresponding amplitude and a corresponding phase delay; calculating a scaling factor for each detector channel, each scaling factor equal to the ratio of the corresponding window signal amplitude and a normalization signal amplitude; and subtracting the product of the corresponding scaling factor and a phase-shifted window reference signal from each detector signal, thereby providing a corrected detector signal for each detector channel. 10. The method of claim 9, wherein the window signals are measured without a sample on the window assembly.
11. The method of claim 9, wherein the window signals are measured with a blanking sample on the window assembly.
12. The method of claim 9, wherein the normalization signal amplitude is measured concurrently with the measurement of the window signals.
13. The method of claim 9, wherein the normalization signal amplitude is generated by a resistance temperature device coupled to the window assembly.
14. The method of claim 9, wherein the window assembly comprises a heater and the normalization signal amplitude is indicative of a current flowing through the heater.
15. The method of claim 9, wherein determining the window reference phase shift comprises finding the value of the window reference phase shift which maximizes a sensitivity of the analyte detection system.
16. The method of claim 9, wherein determining the window reference phase shift comprises finding the value of the window reference phase shift which minimizes a sample signal amplitude.
17. The method of claim 9, wherein the window reference signal in measured with a sample on the window assembly.
18. A method for improving the sensitivity of a noninvasive infrared analyte detection system having a window assembly and a plurality of detector channels, each detector channel configured to generate signals in response to infrared emissions at a characteristic wavelength, the method comprising:
providing a reference detector channel, the reference detector channel configured to generate reference signals in response to infrared emissions at a reference wavelength; measuring a reference window signal using the reference detector channel, the reference window signal having an amplitude corresponding to infrared emissions at the reference wavelength from the window assembly; measuring a plurality of window signals using the plurality of detector channels, each window signal having an amplitude corresponding to infrared emissions at the characteristic wavelength of the detector channel from the window assembly; calculating a scaling factor for each detector channel, each scaling factor equal to the ratio of the corresponding window signal amplitude and the reference window signal amplitude; measuring a reference detector signal using the reference detector channel, the reference detector signal having an amplitude corresponding to infrared emissions at the reference wavelength from the sample and the window assembly; measuring a plurality of detector signals using the plurality of detector channels, each detector signal having an amplitude corresponding to infrared emissions at the characteristic wavelength of the detector channel from the sample and the window assembly; and calculating a corrected detector signal for each detector channel, the corrected detector signal equal to the corresponding detector signal minus the product of the scaling factor and the reference detector signal from each detector signal. 19. The method of claim 18, wherein the reference wavelength is approximately 5 microns.
20. The method of claim 18, wherein the reference detector channel is isolated from other portions of the analyte detection system.
21. The method of claim 18, wherein the reference window signal is measured with no sample on the window assembly.
22. The method of claim 18, wherein the reference window signal is measured with a blanking sample on the window assembly.
23. The method of claim 18, wherein the plurality of window signals are measured concurrently with the measurement of the reference window signal.
24. The method of claim 18, wherein the reference detector signal is measured with a sample on the window assembly.
25. The method of claim 18, wherein the plurality of detector signals is measured with a sample on the window assembly.
26. The method of claim 18, wherein the plurality of detector signals is measured concurrently with the measurement of the reference detector signal.
27. A method of enhancing the accuracy of an analyte measuring system, wherein said analyte measuring system comprises at least one infrared radiation detector and at least one window through which infrared radiation from a sample to be tested is received, said method comprising:
estimating at least one characteristic of the detector signal produced by infrared radiation generated by said window; and compensating the total received detector signal using at least in part said estimated characteristic. 28. A method of enhancing the accuracy of an analyte measuring system, wherein said analyte measuring system comprises at least one infrared radiation detector responsive to infrared radiation in a wavelength range and at least one window through which infrared radiation from a sample to be tested is received, said method comprising:
reducing the response of the analyte measuring system to infrared radiation emitted by the window, wherein said reducing comprises increasing the transmission of the window in the wavelength range. 29. The method of claim 28, wherein the wavelength range is between approximately 8 microns and approximately 12 microns and the transmission of the window in the wavelength range is greater than approximately 60%.
30. The method of claim 28, wherein the wavelength range is between approximately 8 microns and approximately 12 microns and the transmission of the window in the wavelength range is greater than approximately 70%.
31. A method of enhancing the accuracy of an analyte measuring system, wherein said analyte measuring system comprises a first infrared radiation detector generating a first signal having a first phase shift in response to infrared radiation in a first wavelength range, a second infrared radiation detector generating a second signal having a second phase shift in response to infrared radiation in a second wavelength range, and at least one window through which infrared radiation from a sample to be tested is received, said method comprising:
reducing the response of the analyte measuring system to infrared radiation emitted by the window, wherein said reducing comprises selecting the first wavelength range and the second wavelength range such that the first phase shift and the second phase shift are approximately equal. 32. A method of enhancing the accuracy of an analyte measuring system, wherein said analyte measuring system comprises a first infrared radiation detector generating a first signal having a first phase shift in response to infrared radiation in a first wavelength range, a second infrared radiation detector generating a second signal having a second phase shift in response to infrared radiation in a second wavelength range, and at least one window through which infrared radiation from a sample to be tested is received, said method comprising:
reducing the response of the analyte measuring system to infrared radiation emitted by the window, wherein said reducing comprises selecting the first wavelength range and the second wavelength range such that the difference between the first phase shift and the second phase shift is minimized. 33. A method of enhancing the accuracy of an analyte measuring system, wherein said analyte measuring system comprises at least one infrared radiation detector responsive to infrared radiation in a wavelength range and at least one window through which infrared radiation from a sample to be tested is received, said sample coupled to said window, said method comprising:
stabilizing the coupling between the sample and the window by placing a fluid film between the sample and the window. 34. The method of claim 33, wherein the fluid film comprises mineral oil.
CLAIM OF PRIORITY This application claims priority from U.S. Provisional Application No. 60/332,322, filed Nov. 21, 2001, which is incorporated in its entirety by reference herein.
The present invention relates generally to optical noninvasive analyte detection systems, and more particularly to methods for correcting the output of such systems to remove contributions not from the sample under study.
Millions of diabetics are forced to draw blood on a daily basis to determine their blood glucose levels. In addition, the detection of other blood constituents, such as the determination of the concentration of alcohol in the bloodstream, often requires blood withdrawal in order to perform a precise analysis thereof. A search for a noninvasive methodology to accurately determine blood constituent levels has been substantially expanded in order to alleviate the discomfort of these individuals. A significant advance in the state of the art of noninvasive blood constituent analysis has been realized by the development of spectrometers, including �thermal gradient� spectrometers, which analyze the absorbance of particular wavelengths of infrared (�IR�) energy passed through and/or emitted by a sample of tissue. These spectroscopic analytical devices typically employ a window or lens for admitting infrared energy into the device for analysis by infrared detectors.
SUMMARY OF THE INVENTION In accordance with certain embodiments described herein, an analyte detection system non-invasively determines the concentration of an analyte in a sample generating a sample infrared signal indicative of the concentration of the analyte in the sample. The detection system includes a window assembly for receiving the sample infrared signal. The window assembly is adapted to allow the sample infrared signal to transmit therethrough, and generates a window infrared signal. The detection system further includes at least one detector configured to receive both the window infrared signal and the sample infrared signal transmitted through the window assembly. The detector is further adapted to generate a detector signal in response thereto. The detection system further includes a correction module configured to generate a corrected detector signal indicative of the concentration of the analyte in the sample.
In accordance with other embodiments described herein, a method improves the sensitivity of a noninvasive infrared analyte detection system having a window assembly and a plurality of detector channels. Each detector channel generates a detector signal in response to infrared emissions from a sample and infrared emissions from the window assembly. The method comprises measuring a window signal for each detector channel. Each window signal has a corresponding amplitude and a corresponding phase delay. The method further comprises calculating a scaling factor for each detector channel. Each scaling factor is equal to the ratio of the corresponding window signal amplitude and a normalization signal amplitude. The method further comprises subtracting the product of the corresponding scaling factor and a phase-shifted window reference signal from each detector signal, thereby providing a corrected detector signal for each detector channel.
In accordance with still other embodiments described herein, a method improves the sensitivity of a noninvasive infrared analyte detection system having a window assembly and a plurality of detector channels. Each detector channel is configured to generate signals in response to infrared emissions at a characteristic wavelength. The method comprises providing a reference detector channel. The reference detector channel is configured to generate reference signals in response to infrared emissions at a reference wavelength. The method further comprises measuring a reference window signal using the reference detector channel. The reference window signal has an amplitude corresponding to infrared emissions at the reference wavelength from the window assembly. The method further comprises measuring a plurality of window signals using the plurality of detector channels. Each window signal has an amplitude corresponding to infrared emissions at the characteristic wavelength of the detector channel from the window assembly. The method further comprises calculating a scaling factor for each detector channel. Each scaling factor is equal to the ratio of the corresponding window signal amplitude and the reference window signal amplitude. The method further comprises measuring a reference detector signal using the reference detector channel. The reference detector signal has an amplitude corresponding to infrared emissions at the reference wavelength from the sample and the window assembly. The method further comprises measuring a plurality of detector signals using the plurality of detector channels. Each detector signal has an amplitude corresponding to infrared emissions at the characteristic wavelength of the detector channel from the sample and the window assembly. The method further comprises calculating a corrected detector signal for each detector channel. The corrected detector signal is equal to the corresponding detector signal minus the product of the scaling factor and the reference detector signal from each detector signal.
In accordance with still other embodiments described herein, a method enhances the accuracy of an analyte measuring system. The analyte measuring system comprises at least one infrared radiation detector and at least one window through which infrared radiation from a sample to be tested is received. The method comprises estimating at least one characteristic of the detector signal produced by infrared radiation generated by said window. The method further comprises compensating the total received detector signal using at least in part said estimated characteristic.
In accordance with still other embodiments described herein, a method enhances the accuracy of an analyte measuring system. The analyte measuring system comprises at least one infrared radiation detector responsive to infrared radiation in a wavelength range and at least one window through which infrared radiation from a sample to be tested is received. The method comprises reducing the response of the analyte measuring system to infrared radiation emitted by the window. The reducing comprises increasing the transmission of the window in the wavelength range.
In accordance with still other embodiments described herein, a method enhances the accuracy of an analyte measuring system. The analyte measuring system comprises a first infrared radiation detector generating a first signal having a first phase shift in response to infrared radiation in a first wavelength range, a second infrared radiation detector generating a second signal having a second phase shift in response to infrared radiation in a second wavelength range, and at least one window through which infrared radiation from a sample to be tested is received. The method comprises reducing the response of the analyte measuring system to infrared radiation emitted by the window. The reducing comprises selecting the first wavelength range and the second wavelength range such that the first phase shift and the second phase shift are approximately equal.
In accordance with still other embodiments described herein, a method enhances the accuracy of an analyte measuring system. The analyte measuring system comprises a first infrared radiation detector generating a first signal having a first phase shift in response to infrared radiation in a first wavelength range, a second infrared radiation detector generating a second signal having a second phase shift in response to infrared radiation in a second wavelength range, and at least one window through which infrared radiation from a sample to be tested is received. The method comprises reducing the response of the analyte measuring system to infrared radiation emitted by the window. The reducing comprises selecting the first wavelength range and the second wavelength range such that the difference between the first phase shift and the second phase shift is minimized.
In accordance with still other embodiments described herein, a method enhances the accuracy of an analyte measuring system. The analyte measuring system comprises at least one infrared radiation detector responsive to infrared radiation in a wavelength range and at least one window through which infrared radiation from a sample to be tested is received. The sample is coupled to said window. The method comprises stabilizing the coupling between the sample and the window by placing a fluid film between the sample and the window.
FIG. 18 schematically illustrates the sum of the two infrared signals at the detector represented by the sum of two vectors.
FIG. 19 schematically illustrates the differential phase drift of the RTD signal and of the difference between the glucose detector and the reference detector signals as functions of time.
FIG. 20 schematically illustrates the amplitudes of the RTD signal, the glucose signal, and the reference signal as functions of time.
FIG. 21 schematically illustrates the differential phase (in degrees) plotted as a function of the ratio of the RTD amplitude to the detector amplitude.
FIG. 22 schematically illustrates the optical transmission of various CVD-diamond windows.
FIG. 23 schematically illustrates the differential phase drift for continuous measurements of three measurement runs for two trials.
FIG. 24 schematically illustrates the detector signal amplitude change for continuous measurements of three measurement runs for two trials.
FIG. 25 schematically illustrates the detector signal phase change for continuous measurements of three measurement runs for two trials.
FIG. 26 schematically illustrates the initial RTD amplitude plotted against the initial detector amplitude for a series of measurements comparing dry skin samples (in this case, human arms) with dry skin samples plus mineral oil.
FIG. 27 schematically illustrates a plot of g(�, δ) as a function of � for various values of δ in millidegrees.
FIG. 28 schematically illustrates the ratio of the RTD signal to the detector amplitude at the beginning of each measurement plotted against the differential phase at the beginning of each measurement for a series of dry arms measured over three days.
FIG. 29 schematically illustrates the accuracy needed for the amplitude of the correction signal as a function of the phase angle difference between the two spectral lines over a given range for the noninvasive system.
FIGS. 30A-E schematically illustrate various exemplary embodiments of the window assembly.
FIG. 31 is a flow diagram of an embodiment of a method for improving the sensitivity of a noninvasive infrared analyte detection system having a window assembly and a plurality of detector channels.
FIG. 32A schematically illustrates a exemplary plot of the measured phase difference as a function of glucose concentration for five calibration samples with known glucose concentration levels.
FIG. 32B schematically illustrates an exemplary plot of the sensitivity as a function of the window reference phase shift.
FIG. 33 schematically illustrates the wavelength dependence of the window transmission.
FIG. 34 is a flow diagram of an embodiment of a method for improving the sensitivity of a noninvasive infrared analyte detection system having a window assembly and a plurality of detector channels.
FIG. 35 schematically illustrates the scaling factors for various wavelengths in an exemplary embodiment.
FIG. 36 schematically illustrates the measured differential phase before and after performing the optical window signal correction in an exemplary embodiment.
FIG. 37A schematically illustrates the amplitudes of the detector signal, the sample signal, and the window signal for one of the detector channels.
FIG. 37B schematically illustrates the ratio of the window signal to the sample signal for one of the detector channels.
DETAILED DESCRIPTION Although certain preferred embodiments and examples are disclosed below, it will be understood by those skilled in the art that the invention extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses of the invention and obvious modifications and equivalents thereof. Thus, it is intended that the scope of the invention herein disclosed should not be limited by the particular disclosed embodiments described below.
FIG. 4 is a top schematic view of a preferred arrangement of the window assembly 12 (of the types shown in FIGS. 2 or 2A) and the cold reservoir 16, and FIG. 5 is a top schematic view of an alternative arrangement in which the window assembly 12 directly contacts the cooling system 14. The cold reservoir 16/cooling system 14 preferably contacts the underside of the window assembly 12 along opposing edges thereof, on either side of the heater layer 34. With thermal conductivity thus established between the window assembly 12 and the cooling system 14, the window assembly can be cooled as needed during operation of the noninvasive system 10. In order to promote a substantially uniform or isothermal temperature profile over the upper surface of the window assembly 12, the pitch distance between centerlines of adjacent heater elements 38 may be made smaller (thereby increasing the density of heater elements 38) near the region(s) of contact between the window assembly 12 and the cold reservoir 16/cooling system 14. As a supplement or alternative, the heater elements 38 themselves may be made wider near these regions of contact. As used herein, �isothermal� is a broad term and is used in its ordinary sense and refers, without limitation, to a condition in which, at a given point in time, the temperature of the window assembly 12 or other structure is substantially uniform across a surface intended for placement in thermally conductive relation to the material sample S. Thus, although the temperature of the structure or surface may fluctuate over time, at any given point in time the structure or surface may nonetheless be isothermal.
In the illustrated embodiment, the heat spreader layer 412 may be constructed according to the following dimensions, which are to be understood as exemplary; accordingly the dimensions may be varied as desired. The heat spreader layer 412 has an overall length and width of about 1.170″, with a central opening of about 0.590″ long by 0.470″ wide. Generally, the heat spreader layer 412 is about 0.030″ thick; however, the rails 416 extend a further 0.045″ above the basic thickness of the heat spreader layer 412. Each rail 416 has an overall length of about 0.710″; over the central 0.525″ of this length each rail 416 is about 0.053″ wide. On either side of the central width each rail 416 tapers, at a radius of about 0.6″, down to a width of about 0.023″. Each opening 424 is about 0.360″ long by about 0.085″ wide, with comers rounded at a radius of about 0.033″.
In the illustrated embodiment, conductive layer 414 may be constructed according to the following dimensions, which are to be understood as exemplary; accordingly the dimensions may be varied as desired. The conductive layer 414 has an overall length and width of about 1.170″, with a central opening of about 0.590″ long by 0.470″ wide. Generally, the conductive layer 412 is about 0.035″ thick; however, the protrusions 426 extend a further 0.075″-0.085″ above the basic thickness of the conductive layer 414. Each protrusion 426 is about 0.343″ long by about 0.076″ wide, with comers rounded at a radius of about 0.035″.
Still referring to FIG. 1, the collimator 22 comprises a tube with an inner surface coating which is highly reflective and minimally absorptive in infrared wavelengths, preferably a polished gold coating. The tube itself may be fabricated from a another rigid material such as aluminum, nickel or stainless steel, as long as the inner surfaces are coated or otherwise treated to be highly reflective. Preferably, the collimator 22 has a rectangular cross-section, although other cross-sectional shapes, such as other polygonal shapes or circular, parabolic or elliptical shapes, may be employed in alternative embodiments. The inner walls of the collimator 22 diverge as they extend away from the mixer 20. Preferably, the inner walls of the collimator 22 are substantially straight and form an angle of about 7 degrees with respect to the longitudinal axis A�A. The collimater 22 aligns the infrared energy E to propagate in a dirtion that is generally parrel to the longitudinal axis A�A of the mixer 20 and the collimator 22, so that the infrared energy E will strike the surface of the filters 24 at an angle as close to 90 degrees as possible.
Additional details not necessary to repeat here may be found in U.S. Pat. No. 6,198,949, titled SOLID-STATE NON-INVASIVE INFRARED ABSORPTION SPECTROMETER FOR THE GENERATION AND CAPTURE OF THERMAL GRADIENT SPECTRA FROM LIVING TISSUE, issued Mar. 6, 2001; U.S. Pat. No. 6,161,028, titled METHOD FOR DETERMINING ANALYTE CONCENTRATION USING PERIODIC TEMPERATURE MODULATION AND PHASE DETECTION, issued Dec. 12, 2000; U.S. Pat. No. 5,877,500, titled MULTICHANNEL INFRARED DETECTOR WITH OPTICAL CONCENTRATORS FOR EACH CHANNEL, issued on Mar. 2, 1999; U.S. patent application Ser. No. 09/538,164, filed Mar. 30, 2000 and titled METHOD AND APPARATUS FOR DETERMINING ANALYTE CONCENTRATION USING PHASE AND MAGNITUDE DETECTION OF A RADIATION TRANSFER FUNCTION; U.S. Provisional Patent Application No. 60/336,404, filed Oct. 29, 2001, titled WINDOW ASSEMBLY; U.S. Provisional Patent Application No. 60/340,435, filed Dec. 12, 2001, titled CONTROL SYSTEM FOR BLOOD CONSTITUENT MONITOR; U.S. Provisional Patent Application No. 60/340,654, filed Dec. 12, 2001, titled SYSTEM AND METHOD FOR CONDUCTING AND DETECTING INFRARED RADIATION; U.S. Provisional Patent Application No. 60/336,294, filed Oct. 29, 2001, titled METHOD AND DEVICE FOR INCREASING ACCURACY OF BLOOD CONSTITUENT MEASUREMENT; and U.S. Provisional Patent Application No. 60/339,116, filed Nov. 7, 2001, titled METHOD AND APPARATUS FOR IMPROVING CLINICALLY SIGNIFICANT ACCURACY OF ANALYTE MEASUREMENTS. All of the above-mentioned patents, patent applications and publications (including any appendices thereto) are hereby incorporated by reference herein and made a part of this specification.
The filter 230 permits electromagnetic radiation of selected wavelengths to pass through and impinge upon the cuvette/sample element 240. Preferably, the filter 230 permits radiation at least at about the following wavelengths to pass through to the cuvette/sample elements: 3.9, 4.0 μm, 4.05 μm, 4.2 μm, 4.75, 4.95 μm, 5.25 μm, 6.12 μm, 7.4 μm, 8.0 μm, 8.45 μm, 9.25 μm, 9.65 μm, 10.4 μm, 12.2 μm. In another embodiment, the filter 230 permits radiation at least at about the following wavelengths to pass through to the cuvette/sample element: 5.25 μm, 6.12 μm, 6.8 μm, 8.03 μm, 8.45 μm, 9.25 μm, 9.65 μm, 10.4 μm, 12 μm. In still another embodiment, the filter 230 permits radiation at least at about the following wavelengths to pass through to the cuvette/sample element: 6.85 μm, 6.97 μm, 7.39 μm, 8.23 μm, 8.62 μm, 9.02 μm, 9.22 μm, 9.43 μm, 9.62 μm, and 10.10 μm. The sets of wavelengths recited above correspond to specific embodiments within the scope of this disclosure. Furthermore, other subsets of the foregoing sets or other combinations of wavelengths can be selected. Finally, other sets of wavelengths can be selected within the scope of this disclosure based on cost of production, development time, availability, and other factors relating to cost, manufacturability, and time to market of the filters used to generate the selected wavelengths, and/or to reduce the total number of filters needed.
The distance between the windows 244, 246 comprises an optical pathlength and can be between about 1 μm and about 100 μm. In one embodiment, the optical pathlength is between about 10 μm and about 40 μm, or between about 25 μm and about 60 m, or between about 30 μm and about 50 μm. In still another embodiment, the optical pathlength is about 25 μm. The transverse size of each of the windows 244, 246 is preferably about equal to the size of the detector 250. In one embodiment, the windows are round with a diameter of about 3 mm. In this embodiment, where the optical pathlength is about 25 μm the volume of the sample cell 242 is about 0.177 μL. In one embodiment, the length of the sample supply passage 248 is about 6 mm, the height of the sample supply passage 248 is about 1 mm, and the thickness of the sample supply passage 248 is about equal to the thickness of the sample cell, e.g., 25 μm. The volume of the sample supply passage is about 0.150 μL. Thus, the total volume of the cuvette 240 in one embodiment is about 0.327 μL. Of course, the volume of the cuvette 240/sample cell 242/etc. can vary, depending on many variables, such as the size and sensitivity of the detectors 250, the intensity of the radiation emitted by the source 220, the expected flow properties of the sample, and whether flow enhancers (discussed below) are incorporated into the cuvette 240. The transport of fluid to the sample cell 242 is achieved preferably through capillary action, but may also be achieved through wicking, or a combination of wicking and capillary action.
II. Window Signal Correction While the majority of the IR signal collected by the detectors 28 comes from the material sample S, IR emissions from the window assembly 12 itself can contribute approximately 10-20% of the total signal. During operation of the noninvasive system 10, the window assembly 12 produces infrared radiation that is mixed at the detectors 28 with the infrared radiation from the material sample S. This �window signal� contribution to the total signal can reduce the sensitivity of the glucose measurement and is a major source of differential phase drift, thereby degrading the accuracy of calculations of the analyte concentration. It is therefore desirable to separate the window signal contribution from the total signal and to reduce or eliminate the window signal contribution to improve the accuracy of the analyte-concentration readings.
A. Model of the Total Signal and the Window Signal Contribution
It is helpful to construct a mathematical model of the total signal and the window signal contribution in order to reduce or eliminate the window signal contribution from the total signal.
1. Phase Relation Between the Detector Signal and the Sample Signal
There are at least two signals impinging on each infrared detector 28 resulting in the �detector signal,� (i) the �sample signal� due to infrared radiation from the material sample S and (ii) the �window signal� due to infrared radiation from the window assembly 12. As schematically illustrated in FIG. 18, the sum of the two infrared signals at the detector can be represented by the sum of two vectors. Defining the phase of the window signal as zero, the detector signal D(t) can be expressed as:
D(t)=S cos(ωt−φ)=A cos(ωt−θ)+B cos ωt (1) where S = ( A ⁢ ⁢ sin ⁢ ⁢ θ ) 2 + ( A ⁢ ⁢ cos ⁢ ⁢ θ + B ) 2 ⁢ ⁢ and ( 2 ) tan ⁢ ⁢ ϕ = A ⁢ ⁢ sin ⁢ ⁢ θ A ⁢ ⁢ cos ⁢ ⁢ θ + B . ( 3 ) In Equations (1)-(3), ω is the angular frequency of the temperature cycle, S and φ are respectively the amplitude and phase of the detector signal, A and θ are respectively the amplitude and phase of the sample signal, and B is the amplitude of the window signal.
The phase (φ) measured by the detector is different from the phase (θ) of the sample signal. By using FIG. 18, the phase difference between the measured detector signal and window signal can be expressed as: sin ⁢ ⁢ ( θ - ϕ ) = B ⁢ ⁢ sin ⁢ ⁢ θ S . ( 4 ) Typically, for the noninvasive system 10, the ratio B/S is less than or equal to approximately 0.2 and the sample signal phase (θ) is less than or equal to approximately 15 degrees. Therefore, the right-hand side of Equation (4) is small. Using the small-angle approximation for sin(θ−φ) and rearranging terms, the basic relation of the measured detector signal phase (φ) to the sample signal phase (θ), detector signal amplitude (S), and window signal amplitude (B) can be expressed as: ϕ = θ - B S ⁢ sin ⁢ ⁢ θ . ( 5 ) For multiple detectors, subscripts are used to refer to each detector parameter. For detector �j� the measured detector signal phase is: ϕ j = θ j - B j S j ⁢ ⁢ sin ⁢ ⁢ θ j . ( 6 ) 2. Phase Change Due to Analyte Concentration
Consider a two-detector system where Detector #1 is sensitive to both the sample and the analyte and the Detector #2 is sensitive to only the sample. Let the amplitude ratios remain constant throughout the measurement. The phase angles of the two sample signals at two different analyte concentrations can be expressed as:
Detector #1 Detector #2 Concentration a θ1 θ2 Concentration b θ1 + δθ1 θ2 The phase differences between the two detector signals at each concentration are defined as follows:
Δφa≡(φ1−φ2)a Δφb≡(φ1−φ2)b (7)
and then, using Equation (6): Δ ⁢ ⁢ ϕ a = ( θ 1 - θ 2 ) - [ B 1 S 1 ⁢ ⁢ sin ⁢ ⁢ θ 1 - B 2 S 2 ⁢ ⁢ sin ⁢ ⁢ θ 2 ] ⁢ ⁢ and ( 8 ) Δ ⁢ ⁢ ϕ b = [ ( θ 1 + δ ⁢ ⁢ θ 1 ) - θ 2 ] - [ B 1 S 1 ⁢ ⁢ sin ⁢ ⁢ ( θ 1 + δ ⁢ ⁢ θ 1 ) - B 2 S 2 ⁢ ⁢ sin ⁢ ⁢ θ 2 ] . ( 9 ) The phase change due to change in analyte concentration is very small, allowing expansion of sin(θ1+δθ1) in equation (9): Δ ⁢ ⁢ ϕ b = [ ( θ 1 + δ ⁢ ⁢ θ 1 ) - θ 2 ] - [ B 1 S 1 ⁢ ( ⁢ sin ⁢ ⁢ θ 1 + δ ⁢ ⁢ θ 1 ⁢ cos ⁢ ⁢ θ 1 ) - B 2 S 2 ⁢ ⁢ sin ⁢ ⁢ θ 2 ] . ( 10 ) Rearranging terms and using Equation (8), the differential phase change (Δφb−Δφa) between the two detector signals can be expressed as: ( Δ ⁢ ⁢ ϕ b - Δ ⁢ ⁢ ϕ a ) = δ ⁢ ⁢ θ 1 ⁡ ( 1 - B 1 S 1 ⁢ ⁢ cos ⁢ ⁢ θ 1 ) . ( 11 ) Equation (11) predicts that the differential phase change measured by the detectors due to the analyte concentration is less than the actual differential phase change (δθ1) from the sample signal. Thus, the window signal contribution to the detector signal reduces the sensitivity of the analyte measurements.
3. Differential Phase Drift
When the sample and window signal amplitudes are not constant during a measurement, the phase of each detector will change. This change is not associated with a change in analyte concentration, but occurs because the ratio of the window signal amplitude (B) to the sample signal amplitude (S) is not constant. With the sample signal phases (θ1, θ2) held constant, Equation (8) illustrates that allowing the amplitude ratios (B1/S1, B2/S2) to vary over time results in variation of the differential phase (Δφ), which appears as a baseline drift in the detector signal.
Differential phase drift has been observed in glucose measurements from humans. FIGS. 19 and 20 illustrate typical glucose concentration data taken from a human subject with a dry arm and no coupling agent. FIG. 19 illustrates the differential phase drift, and FIG. 20 illustrates the amplitudes of the infrared and RTD signals. Because the RTD measures the temperature of the window, its amplitude should be a reasonable measure of the amplitude of the infrared signal emitted by the window. In FIG. 19, the top line shows drift in the differential phase as a function of time. The total drift is approximately 230 millidegrees. In FIG. 20, the top two lines show the relative amplitudes of the detector signals. Both signals increase approximately 25% during the measurement. The third line shows the relative amplitude of the RTD signal, which declines approximately 10%.
The data of FIGS. 19 and 20 were analyzed using the assumption that the window signal has the same value at each detector, as does the detector signal. Under this assumption, the differential phase as a function of time can be expressed as: Δ ⁢ ⁢ ϕ a ⁡ ( t ) = ( θ 1 - θ 2 ) - B ⁡ ( t ) S ⁡ ( t ) ⁢ ( sin ⁢ ⁢ θ 1 - sin ⁢ ⁢ θ 2 ) . ( 12 ) where Δθa(t), B(t), and S(t) are functions of time, because the amplitudes of the window signal and the skin sample signal are changing with time. FIG. 21 illustrates the differential phase Δθa(t) (in degrees) plotted as a function of the ratio of the RTD amplitude to the detector amplitude (S(t)). Taking the RTD amplitude as being proportional to the window signal (B(t)), FIG. 21 illustrates that the differential phase is linearly dependent on the ratio B(t)/S(t), as predicted by Equation (12).
Stabilizing the signal amplitudes from the sample and the window reduces or eliminates the time-dependent differential phase drift. This effect has been observed in measurements from water-glucose solutions where the amplitudes of the detector and RTD signals are constant throughout the measurement. Measurements from such water-glucose solutions have exhibited a reduction in the instrument's sensitivity without a differential phase drift.
However, the major source of the changing amplitudes with human subjects is the changing contact between the sample skin and the window. As the measurement proceeds, the skin conforms more closely to the window surface, thereby increasing the area of the skin in contact with the window and increasing the amplitude of the sample signal. The increased contact increases the thermal load on the window, thereby reducing the temperature swing and reducing the amplitude of the window signal. These two effects result in an overall change in the amplitude ratio B(t)/S(t) as the measurement proceeds.
The amplitude ratio for detector j can be expressed as: B j S j = κ j ⁢ β ( 13 ) where κj is a proportionality constant that relates the window signal amplitude at detector j to the amplitude of the RTD signal, and β is the ratio of the RTD signal amplitude to the detector signal amplitude.
Substituting Equation (13) into Equation (8), the differential phase drift can be expressed as:
Δφa(t)=(θ1−θ2)−β(t)(κ1 sin θ1−κ2 sin θ2). (14)
The phase angles (θ1 and θ2) each change by the same amount as a function of the contact between the sample and the window. This change of the phase angles can be expressed as:
θ1→θ1+θc(t)θ2→θ2+θc(t) (15)
where θj is the constant phase angle for detector j introduced by the sample, and θc(t) is the phase angle change due to the changing contact between the sample and the window. By substituting these values into Equation (14), the differential phase drift as a function of the time-varying contact can then be expressed as:
Δφa(t)=(θ1−θ2)−β(t)[κ1 sin(θ1+θc(t))−κ2 sin(θ2−θc(t))]. (16)
4. Reduction of the Window Signal Contribution
A number of design strategies may be employed with the noninvasive system 10 to reduce the effects of the differential phase drift from the window signal contribution on measurement accuracy. Using Equation (16) with the simplifying assumption that the proportionality constant (κ) is the same for both detectors, the differential phase drift Δφa(t) can be expressed as:
Δφa(t)=(θ1−θ2)−κβ(t)[sin(θ1+θc(t))−sin(θ2+θc(t))]. (17)
sin A−sin B=2 sin �(A−B)cos �(A+B) (18)
the differential phase drift can be expressed as:
Δφa=(θ1−θ2)−{2κ sin[�(θ1−θ2)]�β(t) cos[�(θ1+θ2)+θc(t)]}. (19)
The bracketed second term on the right-hand side of Equation (19) contains two factors that describe the effect of the window signal on the differential phase drift. The first factor (2κ sin[�(θ1−θ2)]) is a constant scale factor corresponding to the magnitude of the differential phase drift due to the window signal effect. The second factor corresponds to the time-dependent changes of the differential phase drift due to the window signal effect. Equation (19) suggests three ways to reduce the magnitude and time dependence of the differential phase drift due to the window effect: (i) reduce the proportionality constant κ by increasing the transmission of the window; (ii) minimize the quantity (θ1−θ2) by choosing filters at wavelengths having similar absorption as the sample; and (iii) minimize the change over time of β and θc by stabilizing the physical contact between the sample S and window assembly 12.
In certain embodiments, the differential phase drift due to the window signal effect is reduced by reducing the proportionality constant κ. The proportionality constant κ relates the magnitude of the window signal at the detector to the magnitude of the RTD or heater-grid signal associated with the window's temperature oscillation. Reducing the proportionality constant κ can be achieved by reducing the emissivity, or, equivalently, increasing the transmission of the window, thereby reducing the magnitude of the differential phase drift due to the window signal. FIG. 22 illustrates the optical transmission of various CVD-diamond windows obtained from DeBeers Industrial Diamonds of Ascot, UK and from Norton Diamond Film of Northboro, Mass. As illustrated in FIG. 22, the window signal amplitude from the window from Norton Diamond Film is less than that of the DeBeers window.
In certain embodiments, the window effect is reduced by minimizing the quantity (θ1−θ2) by choosing filters, for analysis or reference, which transmits spectral lines that are similarly absorbed by the samples. To demonstrate this, the same subject was measured during two clinical trials (Trial A and Trial B). For both trials, the glucose detector had a 9.54 micron filter. Trial A used a reference detector with a 10.8 micron filter and Trial B used a reference detector with a 8.5 micron filter. The table below shows the predicted values for θ1 and θ2.
Glucose detector (microns)
Reference detector (microns)
(θ1 − θ2) (degrees)
sin � (θ1 − θ2)
FIGS. 23, 24, and 25 respectively show the differential phase drift, detector signal amplitude change and detector signal phase change for continuous measurements of three measurement runs on Trial A and Trial B. As predicted, the differential phase drift is much less with Trial B even though the amplitude and phase changes of the detector signals are similar between the two trials.
In certain embodiments, the differential phase drift is reduced by stabilizing the contact between the sample S and the window assembly 12 to limit drift of the amplitude of the signals. In certain such embodiments, contact fluids are used to fill in the rough skin surface and to improve the thermal contact between the sample S and the window assembly 12. The choice of contact fluids is limited by the limitation that the contact fluid be transparent in the infrared region of the measurements. Exemplary fluids compatible with embodiments described herein includes, but are not limited to, mineral oil. Mineral oil does not completely eliminate the contact effect, since the amplitude of the skin infrared signal still increases during the measurement, although the contact effect is lessened as compared to that in the dry sample case. FIG. 26 shows the initial RTD amplitude plotted against the initial detector amplitude for a series of measurements comparing dry skin samples (in this case, human arms) with dry skin samples plus mineral oil. The spread of the initial angle is due to the initial contact condition, which changes from measurement to measurement. The differential phase drift during the measurement showed the same reduction with mineral oil.
B. Correction of the Window Signal Contribution
The amplitude and phase of the window signal can be subtracted in the time-domain from the detector signal to obtain the sample signal. In certain embodiments, a second signal, independent of the detector signal, provides information about the window signal amplitude and phase.
1. Correction Signal
A correction signal derived from independent window signal measurements is defined as follows:
C κ(t)=�B cos(ωt−δ) (20)
where � and δdenote respectively the amplitude and phase deviations of the correction signal from the actual window signal. Subtracting the correction signal from the detector signal from Equation (1), the corrected detector signal Dκ(t) can be expressed as:
D κ(t)=D(t)−C κ(t)=A cos(ωt−θ)+B[cos(ωt−� cos(ωt−δ)]. (21)
Combining the two terms in the brackets, the corrected detector signal can be expressed as:
D κ(t)=A cos(ωt−θ)+B κ cos(ωt−δ κ) (22)
where B κ = B ⁢ ( f ⁢ ⁢ sin ⁢ ⁢ δ ) 2 + ( 1 - f ⁢ ⁢ cos ⁢ ⁢ δ ) 2 = B ⁡ ( 1 - f ⁢ ⁢ cos ⁢ ⁢ δ ) ⁢ ⁢ 1 + tan 2 ⁢ ⁢ δ κ ⁢ ⁢ tan ⁢ ⁢ δ κ = - f ⁢ ⁢ sin ⁢ ⁢ δ 1 - f ⁢ ⁢ cos ⁢ ⁢ δ . ( 23 ) Bκ and δκ are the amplitude and phase of the remaining �corrected� window signal of the corrected detector signal Dκ(t).
A time increment can be defined as: Δ ⁢ ⁢ T ≡ δ κ ω ( 24 ) and Dκ(t) at time (t+Δt) can be expressed as:
D κ(t+Δt)=S cos[ωt−(φ−δκ)]=A cos[ωt−(θ−δκ)]+B κ cos ωt. (25)
Equation (25) has the same form as Equation (1) with the substitution:
θ→θ−δκ φ→φ−δκ (26)
Substituting Equations (23) and (26) into Equation (19), the differential phase drift after correction can be expressed as a function of the parameters of the correction signal:
Δφa=(θ1−θ2)−└2(1−� cos δ)√{square root over (1+tan2 δκ)} sin �(θ1−θ2)┘�{κβ(t)cos[�(θ1+θ2)+θc(t)−δκ]} (27)
Using Equation (27), the maximum excursion ΔΦ of the differential phase over a single measurement can be expressed as:
ΔΦ=└2(1−�)√{square root over (1+tan2 δκ)} sin �(θ1−θ2)┘�g(�,δ,βmax,βmin,θc max,θc min) (28)
where g = { κ ⁢ ⁢ β max ⁢ cos ⁡ [ 1 2 ⁢ ( θ 1 + θ 2 ) + θ c ⁢ ⁢ max - δ κ ] } - { κ ⁢ ⁢ β min ⁢ cos ⁡ [ 1 2 ⁢ ( θ 1 + θ 2 ) + θ c ⁢ ⁢ min - δ κ ] } ( 29 ) and where βmax is the maximum value of the amplitude ratio during a measurement, βmin is the minimum value of the amplitude ratio during a measurement, θc max is the maximum value of the phase angle change due to changing contact between the sample and the window during a measurement, and θc min is the minimum value of the phase angle change due to changing contact during a measurement.
Equations (28) and (29) can be used to estimate the dependence of the differential phase drift on the correction signal parameters as follows: g ≈ ⁢ ( κ ⁢ ⁢ β Max - κ ⁢ ⁢ β Min ) ⁢ cos ⁡ [ 1 2 ⁢ ( θ 1 + θ 2 ) + 1 2 ⁢ ( θ c ⁢ ⁢ max = θ c ⁢ ⁢ min ) - δ κ ] g ≈ ⁢ ( κ ⁢ ⁢ Δ ⁢ ⁢ β ) ⁢ cos ⁡ [ 1 2 ⁢ ( θ 1 + θ 2 ) + 1 2 ⁢ ( θ c ⁢ ⁢ max + θ c ⁢ ⁢ min ) - δ κ ] ( 30 ) and
ΔΦ≈2(κΔβm)(1−� cos δ)sin �(θ1−θ2)√{square root over (1+tan2 δκ)} cos[�(θ1+θ2)+�(θc max+θc min)−δκ] (31)
where Δβm is the maximum change in the amplitude ratio over the measurement.
The upper bound for ΔΦ can be estimated by setting the cosine term of Equation (31) equal to one, so that:
ΔΦ≈2(κΔβm)�[sin �(θ1−θ2)]�g(�,δ) (32)
where g ⁡ ( f , δ ) = [ ( 1 - f ⁢ ⁢ cos ⁢ ⁢ δ ) ⁢ 1 + ( - f ⁢ ⁢ sin ⁢ ⁢ δ 1 - f ⁢ ⁢ cos ⁢ ⁢ δ ) 2 ] . ( 33 ) The first two factors of Equation (32) depend on the change of the contact between the sample and the window, and on the absorptions of the analyte and reference spectral lines. The third factor of Equation (32), as shown in Equation (33), depends only on the parameters that correspond to how well the correction signal matches the actual window signal.
FIG. 27 illustrates a plot of g(�, δ) as a function off for various values of δ in millidegrees. When δ is less than approximately 100 millidegrees, g is primarily a function of � and can be expressed as:
ΔΦ≈2(κΔβm)�[sin �(θ1−θ2)]�(1−�) (34)
where g≈(1−�).
The maximum excursion (ΔΦ) of the differential phase drift that can be tolerated during a measurement is related to the required accuracy for the measurement. Rearranging Equation (34), the corresponding accuracy required for � can be expressed as: ( 1 - f ) ≤ Δ ⁢ ⁢ Φ 2 ⁢ ( κ ⁢ ⁢ Δ ⁢ ⁢ β ⁢ m ) ⁡ [ sin ⁢ 1 2 ⁢ ( θ 1 - θ 2 ) ] ( 35 ) where δ is less than approximately 100 millidegrees. In Equation (35), Δβm is the change of the amplitude ratio during a measurement. The same relationship holds for the initial amplitude ratio for successive measurements, where (1−�) can be expressed as: ( 1 - f ) ≤ Δ ⁢ ⁢ Φ 2 ⁢ ( κ ⁢ ⁢ Δ ⁢ ⁢ β o ) ⁡ [ sin ⁢ 1 2 ⁢ ( θ 1 - θ 2 ) ] ( 36 ) where δ is less than approximately 100 millidegrees and Δβo is the change of the initial amplitude ratio for independent measurements.
The most stringent requirement on � is determined by which parameter has a larger variation, Δβm or Δβo. FIG. 28 illustrates the ratio of the RTD signal to the detector amplitude at the beginning of each measurement plotted against the differential phase at the beginning of each measurement for a series of dry arms measured over three days. The change in the starting amplitude ratio β illustrated in FIG. 28 is much larger than what is observed during a measurement. From FIG. 27, the change in β is approximately 80%. The typical value for κβ is around 0.2, so the change from measurement to measurement is approximately: κΔβo=(0.2)(0.8)=0.16. If the accuracy goal for the noninvasive system 10 is 5 milligrams per deciliter, at a sensitivity of 0.2 millidegrees per milligram per deciliter, this error magnitude corresponds to approximately 1 millidegree. Using 1 millidegree (1.7�10−5 radians) for ΔΦ, Equation (36) can be expressed as: ( 1 - f ) ≤ 0.000054 [ sin ⁢ 1 2 ⁢ ( θ 1 - θ 2 ) ] . ( 37 ) FIG. 29 illustrates a plot of Equation (37), which is the desired result. FIG. 29 illustrates the accuracy needed for the amplitude of the correction signal as a function of the phase angle difference between the two spectral lines over a given range for the noninvasive system 10. In embodiments in which the noninvasive system has multiple wavelengths, the correction amplitude for the largest possible angle difference can be specified.
2. Embodiments for Window Signal Correction
Certain embodiments of the window signal correction system involve obtaining a window reference signal and subtracting the window reference signal from the total signal received by the detectors. Two exemplary embodiments, as outlined below, can be used to correct the detector signal for the window signal contribution. These correction system embodiments can be implemented individually, or in cooperation with one another. Embodiments which incorporate both correction systems can advantageously use one correction system to provide a check and balance for the other correction system to ensure that extraneous signals are accurately filtered out of the final signal processed by the noninvasive system 10.
In certain embodiments, an analyte detection system 10 is used for non-invasively determining the concentration of an analyte in a sample from a sample infrared signal indicative of the analyte concentration. The detection system 10 comprises a window assembly 12 for receiving the sample infrared signal. The window assembly 12 is adapted to allow the sample infrared signal to transmit therethrough, and the window assembly 12 generates a window infrared signal. The detection system 10 further comprises at least one detector 28 configured to receive both the window infrared signal and the sample infrared signal transmitted through the window assembly. The detector 28 is adapted to generate a detector signal in response to both the window infrared signal and the sample infrared signal. The detection system 10 further comprises a correction system in electrical communication with the detector 28. The correction system is configured to generate a corrected detector signal indicative of the concentration of the analyte in the sample.
a. Electrical Window Signal Correction
In certain embodiments of the �electrical window signal correction� system, the window assembly 12 comprises two types of electrical components directly connected to the window, each of which can be used to generate an electrical window reference signal. The first type of electrical component is the heater elements 38 which lie on the underside of the window. Current is applied to the heater elements 38 to heat the the window at a frequency of approximately 1 Hz for a given time to raise the temperature of the sample. The second type of electrical component is the RTDs 55 which provide signals indicative of the temperature of the window. Certain embodiments comprise a pair of RTDs 55 located generally in the center of the window, in between the heater elements 38 on the underside of the window. Other embodiments have the RTDs 55 at different positions and orientations, with the RTDs 55 not intersecting the heater elements 38 so as to avoid having the heater elements 38 undesirably impacting the RTD temperature readings. Other embodiments can use other types of electrical components which provide a signal indicative of the infrared emissions from the window assembly 12.
In certain embodiments, the correction system comprises the RTDs 55 while in other embodiments, the correction system comprises the heater elements 38. Use of the RTD signal to monitor the window signal avoids placing any other elements in the optical path, such as a mixer or filter.
Infrared radiation emitted from the window assembly 12 is a function of the temperature distribution throughout the window volume. Because an RTD 55 measures the temperature at only one spot on the window, in certain embodiments, multiple RTDs 55 are used to accurately predict the window signal. Placement of the RTDs 55 on the window assembly 12 can be chosen to allow for more accurate readings and to provide readings from various spots of the window assembly 12.
FIGS. 30A-E schematically illustrate various exemplary embodiments of the window assembly 12. In FIG. 30A, the window assembly 12 has at least one RTD 55 oriented generally parallel to the heater elements 38. In FIG. 30B, the window assembly 12 has at least one RTD 55 on the underside of a first half of the window and oriented at a non-zero angle relative to the heater elements 38 which are on the underside of a second half of the window. In FIG. 30C, the window assembly 12 has at least one RTD 55 on the underside of a first half of the window and oriented at generally perpendicularly to the heater elements 38 which are on the underside of a second half of the window. In FIG. 30D, the window assembly 12 has at least one RTD 55 on the upperside of a first half of the window and oriented at generally perpendicularly to the heater elements 38 which are on the underside of a second half of the window. In FIG. 30E, the window assembly 12 has at least one RTD 55 on the upperside of the window and oriented at a non-zero angle relative to the heater elements 38 and at least one RTD 55 on the underside of the window and oriented generally parallel to the heater elements 38.
In certain embodiments, the window reference signal is generated by a monitor configured to provide a signal indicative of the amount of current flowing through the heater elements 38. In such embodiments, the heater current measurements are generally correlated with the infrared transmissivity of the window assembly 12. In certain embodiments, the monitor directly measures the current flowing through the heater elements 38. Other embodiments measure the voltage across the heater elements 38, the resistance of the heater elements 38, or a combination of the current, voltage, or resistance parameters.
In an exemplary embodiment, a reference point is obtained by blocking out all potential infrared sources other than those directly connected to the window assembly 12. Eliminating the IR contributions from external sources can be accomplished by coating the top surface of a sample window assembly 12 with a material with well-understood IR absorptive and reflective properties (e.g., gold or aluminum). The signals received by the detectors 28 are then specific to the window assembly 12. The detector data as a function of the heater current can then be used to characterize the IR signal generated by the window assembly 12 at different temperatures and can be appropriately subtracted from subsequent readings from an uncoated window assembly 12 to yield the IR signal generated from the sample.
FIG. 31 is a flow diagram of an embodiment of a method 500 for improving the sensitivity of a noninvasive infrared analyte detection system having a window assembly 12 and a plurality of detector channels. Each detector channel generates a detector signal in response to infrared emissions from a sample and infrared emissions from the window assembly 12. The method 500 comprises measuring a window signal for each detector channel in an operational block 510. Each window signal has a corresponding amplitude Wn and a corresponding phase delay ζn. The method 500 further comprises calculating a scaling factor �n for each detector channel in an operational block 520. Each scaling factor �n is equal to the ratio of the corresponding window signal amplitude Wn and a normalization signal amplitude R. The method 500 further comprises determining a window reference phase shift δ in an operational block 530. The method 500 further comprises subtracting the product of the corresponding scaling factor and a window reference signal from each detector signal in an operational block 540, thereby providing a corrected detector signal for each detector channel.
In the operational block 510, a window signal is measured for each detector channel, with each window signal having a corresponding amplitude Wn and a corresponding phase delay ζn. Typically, the window signals are measured while the detector channels are maintained at an approximately stable temperature. In addition, as with detector signals in general, the window signal measurements of certain embodiments are quadrature demodulated and filtered to remove a 0.9375 Hz component.
In certain embodiments, the window signals are measured with no sample on the window assembly, while in other embodiments, the window signals are measured with a blanking sample on the window assembly. Exemplary blanking samples compatible with embodiments described herein include, but are not limited to, non-contact black bodies (NCBB).
The phase delays ζn represent the response times corresponding to each detector channel. In certain embodiments, the phase delays ζn each reflect a delay between the corresponding detector channel and a selected one of the detector channels. For example, detector channel 1 can be used as the selected channel, thus having a phase delay ζ1=0, and the other detector channels have phase delays ζn measured relative to the signal of detector channel 1. In certain embodiments, the input infrared signals received by the detector channels have approximately the same phase as one another. In certain such embodiments, this condition exists because the window assembly has an approximately constant phase over the whole area monitored by the detector channels. In other such embodiments, the detector channels each monitor the same area of the window assembly. As described more fully below, the phase delays ζn are then stored in memory for use in calculating the corrected detector signals of a measurement.
In the operational block 520, a scaling factor �n is calculated for each detector channel. Each scaling factor �n is equal to the ratio of the corresponding window signal amplitude Wn and a normalization signal amplitude R. In certain embodiments, the normalization signal amplitude R is the amplitude of a window reference signal measured concurrently with the measurement of the window signals. In certain such embodiments, as described above, the normalization signal of certain embodiments is generated by one or more RTDs of the window assembly, while in other embodiments, the normalization signal is generated by a monitor configured to provide a normalization signal indicative of the amount of current flowing through the heater elements 38.
The set of scaling factors can be thought of as characterizing the infrared emissions from the window assembly, with each scaling factor expressed as the ratio of a window signal amplitude for each detector channel and a corresponding window reference amplitude. In certain embodiments, the window reference signal is generated with the sample on the window assembly by the same RTD which produced the normalization signal without the sample on the window assembly. As is described more fully below, the scaling factors are stored in memory so they can then be multiplied by measured window reference signals with the sample in place to provide a signal indicative of the infrared emissions from the window assembly 12.
In the operational block 530, a window reference phase shift δ is determined. FIGS. 32A and 32B schematically illustrate one embodiment of determining the window reference phase shift δ. In certain such embodiments, the analyte sensitivity of the analyte detection system is determined by measuring the response of the analyte detection system to known analyte concentrations. The phase difference Δφn for a known analyte concentration is measured and plotted as a function of the analyte concentration. In certain embodiments, an average of the signals from all the detector channels is calculated for each analyte concentration, and the phase difference Δφn is determined by subtracting a reference signal from the average of the detector signals. In certain embodiments, the reference signal is a window reference signal measured concurrently with the measured detector signals. In such embodiments, the reference signal can be expressed as having a phase θref and the phase difference Δφn is determined by subtracting θref from the phase of the average detector signal.
FIG. 32A schematically illustrates a exemplary plot of the measured phase difference Δφn as a function of glucose concentration for five calibration samples with known glucose concentration levels. The slope of the line defined by these points corresponds to the glucose sensitivity of the detector channel (in units of millidegrees per milligram per deciliter).
As described above, the measured detector signals include contributions from the analyte sample and from the window assembly 12. The window signal contributions effectively reduce the sensitivity of the detector channels to analyte concentrations. Therefore, prior to calculating the slope of the measured phase difference Δφn as a function of analyte concentration, it is desirable to subtract the window signal contribution from the measured phase difference Δ100 n. However, in order to use the window reference signal as a measure of the window signal contribution (i.e., the reference signal), the window reference phase shift δ is determined.
In certain embodiments, the window reference phase shift δ is defined to be the phase shift which yields the highest sensitivity. In such embodiments, the phase of the window reference signal is expressed as (θref+δ), and the value of δ is varied to find the value which yields the largest slope of the phase difference versus glucose concentration. FIG. 32B schematically illustrates an exemplary plot of the sensitivity as a function of the window reference phase shift δ. The window reference phase shift δ which provides the highest sensitivity is then stored in memory for use as described below.
In certain other embodiments, the window reference phase shift δ is defined to be the phase shift which results in a minimum value for the amplitude of the sample signal. Referring to FIG. 18, varying the window reference phase shift δ effectively rotates the window signal vector B relative to the sample signal vector A. The window reference phase shift δ is determined by selecting a detector signal S and then varying the window signal phase and subtracting B from S to minimize the sample signal amplitude A. The selected detector signal of certain embodiments is a stable and uniform signal from a calibrated glucose standard, while in other embodiments, the selected detector signal is obtained from the sample under study. The window reference phase shift δ which provides the minimum sample signal amplitude A is then stored in memory for use as described below.
In an operational block 540, the product of the corresponding scaling factor �n and a window reference signal is subtracted from each detector signal, thereby providing a corrected detector signal for each detector channel. In certain embodiments, a detector signal is measured from each detector channel with the sample in place on the window assembly 12 and a window reference signal is measured concurrently. The corrected detector signal for each detector channel can then be expressed as follows:
D n =S n e i(θ n +ζ n ) −� n Be 1(θ ref +δ) where Sn is the amplitude of the measured detector signal, θn is the phase of the measured detector signal, B is the amplitude of the measured window reference signal, and θref is the phase of the measured window reference signal. In certain embodiments, the values of ζn, �n, and δ, having been determined previously, are retrieved from memory.
b. Optical Window Signal Correction
As illustrated by FIG. 33, the window transmission at a wavelength of approximately 4.78 microns is low, approximately 53%. In comparison, at wavelengths of approximately 6.9 microns to approximately 12.2 microns, the window transmission is high, approximately 67%. This wavelength dependence of the window transmission is utilized in certain embodiments of the �optical window signal correction� system to measure the IR signal of the window, which includes the effects of ambient light and the temperature of the surrounding room.
FIG. 34 is a flow diagram of an embodiment of a method 600 for improving the sensitivity of a noninvasive infrared analyte detection system having a window assembly and a plurality of detector channels. Each detector channel is configured to generate signals in response to infrared emissions at a characteristic wavelength. The method 600 comprises providing a reference detector channel in an operational block 610. The reference detector channel is configured to generate reference signals in response to infrared emissions at a reference wavelength. The method 600 further comprises measuring a reference window signal using the reference detector channel in an operational block 620. The reference window signal has an amplitude corresponding to infrared emissions at the reference wavelength from the window assembly. The method 600 further comprises measuring a plurality of window signals using the plurality of detector channels in an operational block 630. Each window signal has an amplitude corresponding to infrared emissions at the characteristic wavelength of the detector channel from the window assembly. The method 600 further comprises calculating a scaling factor for each detector channel in an operational block 640. Each scaling factor is equal to the ratio of the corresponding window signal amplitude and the reference window signal amplitude. The method 600 further comprises measuring a reference detector signal using the reference detector channel in an operational block 650. The reference detector signal has an amplitude corresponding to infrared emissions at the reference wavelength from the sample and the window assembly. The method 600 further comprises measuring a plurality of detector signals using the plurality of detector channels in an operational block 660. Each detector signal has an amplitude corresponding to infrared emissions at the characteristic wavelength of the detector channel from the sample and the window assembly. The method 600 further comprises calculating a corrected detector signal for each detector channel in an operational block 670. The corrected detector signal is equal to the corresponding detector signal minus the product of the scaling factor and the reference detector signal from each detector signal.
In certain such embodiments, a 12-channel analyte detection system can be used, where the analyte detection system comprises a single window assembly and a 3�4 array of detector channels to receive the infrared signal. Each detector channel has a corresponding filter so that each detector channel is sensitive to a particular range of wavelengths.
In the operational block 610, a reference detector channel is provided. In certain embodiments, the reference detector channel has a filter with peak absorption close to the �near IR� range (e.g., at approximately 5 microns). With reference to FIG. 33, the reference detector channel of certain embodiments has a peak absorption at approximately 4.78 microns (denoted by the bold line). Because the transmission of the window assembly 12 at this wavelength is greater than approximately 50%, the signal reaching the detector will contain appreciable signal content from the sample. However, for the purposes of certain embodiments of the method 600, measurements from this reference detector channel are treated as being indicative of infrared radiation emanating solely from the window assembly itself.
In certain embodiments, the reference detector channel is isolated from the other portions of the analyte detection system to avoid mirroring the instrument drift over time that is typical for single-test, intermittent-test, or continuous-test systems. Examples of isolation components include, but are not limited to, insulation, temperature control, or other monitoring options to ensure that the readings of the reference detector remain consistent.
In the operational block 620, the reference detector channel is used to measure a reference window signal. In certain embodiments, the reference window signal is measured with no sample on the window assembly (e.g., no arm or water on the window). In other embodiments, the reference window signal is measured with a blanking sample (e.g., NCBB) on the window assembly using a configuration similar to that used when taking readings with a sample in place. Thus, the amplitude A0 of the reference window signal corresponds to infrared emissions at the reference wavelength from the window assembly.
In the operational block 630, the plurality of detector channels are used to measure a plurality of window signals. In certain embodiments, the window signals are measured with no sample on the window assembly (e.g., no arm or water on the window). In other embodiments, the window signals are measured with a blanking sample (e.g., NCBB) on the window assembly using a configuration similar to that used when taking readings with a sample in place. In certain embodiments, the plurality of window signals are measured concurrently with the measurement of the reference window signal in the operational block 620. Thus, the amplitudes (A1, A2, A3, . . . , An) of the window signals correspond to infrared emissions at the corresponding wavelengths from the window assembly.
In the operational block 640, a scaling factor fn is calculated for each detector channel. Each scaling factor �n is equal to the ratio of the corresponding window signal amplitude and the reference window signal amplitude (i.e., �n=An/A0). The set of scaling factors can be thought of as characterizing the window signal contribution to the plurality of detector channels. FIG. 35 schematically illustrates the scaling factors for various wavelengths in an exemplary embodiment.
In the operational block 650, the reference detector channel is used to measure a reference detector signal. In certain embodiments, the reference detector signal is measured with a sample (e.g., an arm of a patient) on the window assembly. Thus, the reference detector signal has an amplitude B0 corresponding to infrared emissions at the reference wavelength from the sample and the window assembly.
In the operational block 660, the plurality of detector channels are used to measure a plurality of detector signals. In certain embodiments, the plurality of detector signals are measured with a sample (e.g., an arm of a patient) on the window assembly. In certain embodiments, the plurality of detector signals are measured concurrently with the measurement of the reference detector signal. Thus, the amplitudes (B1, B2, B3, . . . , Bn) of the detector signals correspond to infrared emissions at the corresponding wavelengths from the sample and the window assembly. As described above, the window contribution dilutes the sample signal and decreases the sensitivity of the system.
In the operational block 670, a corrected detector signal amplitude is calculated for each detector channel. Each corrected detector signal amplitude is equal to the corresponding detector signal amplitude from each detector signal minus the product of the scaling factor and the reference detector signal amplitude (i.e., Cn=Bn−�n*B0). In certain embodiments, this correction is performed in the amplitude domain prior to demodulation to determine the differential phase. In such embodiments, the voltage of the B0 detector channel signal is multiplied by the scaling factor �n, and this product is subtracted from the voltage of the detector channel signal Bn. The resultant signal Cn is then demodulated to determine the differential phase of the corrected detector signal.
FIG. 36 schematically illustrates the measured differential phase before and after performing the optical window signal correction in an exemplary embodiment. By removing the window signal contribution, the datapoints for each glucose concentration are shifted upwards. In addition, the sensitivity, given by the slope of the line through the datapoints, is higher for the corrected datapoints than for the uncorrected datapoints.
As illustrated in FIG. 36, without performing the optical window signal correction, the slope of the line is approximately 5259 milligram/deciliter/degree, corresponding to a sensitivity of approximately 1.9�10−4 degree/milligram/deciliter. After performing the optical window signal correction, the slope of the line is approximately 4296 milligram/deciliter/degree, corresponding to a sensitivity of approximately 2.3�10−4 degree/milligram/deciliter. Thus, the optical window signal correction resulted in an increase of the sensitivity of approximately 22%. As expected, the root-mean-square of the calculated lines through the two sets of datapoints are approximately equal.
FIG. 37A schematically illustrates the amplitudes of the detector signal, the sample signal, and the window signal for one of the detector channels. FIG. 37B schematically illustrates the ratio of the window signal to the sample signal. The mean ratio is approximately 23%, which matches the increase in sensitivity.
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