Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2001-08-10
2003-05-27
Lateef, Marvin M. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C600S310000, C600S316000, C600S476000, C356S059000
Reexamination Certificate
active
06571117
ABSTRACT:
FEDERALLY SPONSORED RESEARCH
not applicable
SEQUENCE LISTING OR PROGRAM
not applicable
SEQUENCE LISTING
not applicable
REFERENCES CITED
1
. Exceptional Returns: The Economic Value of America's Investment in Medical Research,
report by the Funding First initiative of the Mary Woodard Lasker Cheritable Trust, Washington, D.C., May 2000 (http://www.laskerfoundation.org/fundingfirst)
2. R. Marbach et al.,
Non
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invasive Blood Glucose Assay by Near
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Infrared Diffuse Reflection Spectroscopy of the Human Inner Lip,
Appl. Spectrosc. 47, 875-881 (1993)
3. R. Marbach,
On Wiener Filtering and the Physics Behind Statistical Modeling
, to be published in the Journal of Biomedical Optics (accepted Jul. 6, 2001)
4. R. R. Alfano and S. G. Demos,
Imaging of Objects Based Upon the Polarization or Depolarization of Light
, U.S. Pat. No. 5,847,394 filed Aug. 28, 1996
5. Y. Maekawa et al.,
Non
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invasive Blood Analyzer and Method Using the Same
, U.S. Pat. No. 5,769,076 filed May 2, 1996
6. D. Hochman and M. M. Haglund,
Optical Imaging Methods
, U.S. Pat. No. 5,845,639 filed Nov. 11, 1994
7. R. Marbach and H. M. Heise,
Optical Diffuse Reflectance Accessory for Measurements of Skin Tissue by Near
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Infrared Spectroscopy
, Appl. Optics 34, 610-621 (1995)
FIELD OF THE INVENTION
The invention relates to methods and apparata for improving the tracking accuracy and signal-to-noise ratio of noninvasive blood analysis methods.
BACKGROUND OF THE INVENTION
Recent years have seen significant efforts spent on developing methods that can analyze human blood noninvasively as well as with sufficient accuracy, speed, low cost, minimal discomfort to the patient, and at the point-of-care. The biggest market segment for noninvasive blood analyzers is the diabetes market, because the disease affects a significant fraction of the population and patients are required to perform regular and frequent measurements of their blood glucose concentration. The following discussion will therefore concentrate on glucose as the primary candidate to which this invention can be applied, however, this is only meant in an exemplary way since the invention can be applied equally well to noninvasive measurement methods of other blood constituents, e.g., urea.
A conservative estimate by this author is that >US$ 2 billion have been spent during the last decade on R&D expenses for an accurate noninvasive blood glucose monitor. The reason, of course, is the significant market size and the potential ease with which the existing fingerprick devices could be pushed out of the market by even a fairly expensive noninvasive monitor if only the noninvasive device was accurate enough. Government also has a strong interest in an accurate noninvasive monitor because of the expected decrease in diabetes-related health care costs, which are currently estimated at $92 billion annually in the US [1].
Many different methods for the non-invasive measurement of blood glucose and other blood components-have been proposed. Virtually all are based on optical measurement techniques, i.e., they measure changes in the, e.g., absorbance, scatter, fluorescence, emission, polarization, Raman scatter, or a combination of these effects; in a tissue as a function of the glucose concentration in the blood. Further differences come from the different proposed wavelength regions of the electromagnetic spectrum and locations on the body. Wavelength ranges proposed range from the ultraviolet (&lgr;<400 nm) to the far infrared (&lgr;>20,000 nm) and typical locations proposed include the volar forearm, lip, fingertip, ear lope, and eye. Many of the published claims must be judged with extreme caution, especially in cases when the basic physical relationships are unclear or when the published data is statistically grossly insufficient.
The most promising noninvasive methods are absorbance-based optical measurements performed in diffuse reflection geometry in the near-infrared wavelength region (NIR). Proof of the basic technical feasibility was published in 1993 [2]; however, accuracy was insufficient at about 50 mg/dL root-mean-square (RMS) of measurement error, which is about 3 times larger than the clinically required value. Surprisingly, almost 10 years and $2+billion later, accuracy has not improved substantially since. We will now disclose the reason behind the limitation to accuracy and then, in the descriptive part of this text go on and disclose a method and apparata to overcome it.
The following discussion will concentrate on NIR measurements because these methods have the best chances for commercial success and are therefore prime candidates to which this invention can be applied. However, again, this is not meant in an exclusive way. In fact, the invention can be applied equally well to other noninvasive measurement techniques, based on other optical or even non-optical methods, because the problem solved by the invention applies equally to all noninvasive measurement methods. In the following, whenever words like “optical spectrum,” “optically probed skin volume” etc. are used, they are meant only in an exemplary way.
The accuracy of all non-invasive methods is affected by two types of error, viz. (a) the “spectral error” due to the noise generated by the hardware of the noninvasive device, its sampling interface, and the interfering spectra from the other blood and tissue components and (b) the “tracking error” generated by the fact that the glucose concentration in the probed skin volume is not perfectly correlated with the glucose concentration in the blood. The latter type of error occurs because the glucose concentration in the probed skin volume (PSV) is an average of the glucose dissolved in the interstitial fluid (ISF) and the glucose in the blood. The instantaneous glucose concentration in the ISF (ISFG) can be very different from the glucose concentration in the blood (BG) because of the complicated temporal and spatial relationships between glucose intake and transport, and insulin intake and transport, in the body of a diabetic.
The accuracy of all non-invasive methods is judged by comparison to a high-quality invasive method, which serves as a secondary standard and calibration reference to the noninvasive method. Thus, even if one assumed that both the spectral error of the noninvasive device was zero (i.e., it measured glucose in the PSV (PSVG) with 100% accuracy) and the error of the invasive standard device was zero (i.e., it measured BG with 100% accuracy) then there would still be the difference between the PSVG and the BG causing a difference between the two devices. This is the tracking error, which is counted as an “error” of the noninvasive device, because the value of the invasive reference method is assumed to be “true” by definition. A detailed description of how the tracking error and the spectral error interact and combine to affect the overall measurement accuracy has recently become available [3].
Describing the situation in terms of time functions, it can be said that ISFG is virtually always lagging behind BG when BG goes up. When BG goes down, however, the ISFG in diabetic patients can either be lagging or leading, depending on the status of the complicated push-pull mechanism that controls the ISFG in the PSV. The exact time relationship between BG and ISFG is unpredictable in diabetics and can not be described with just a single number for “lag time.” If one were to plot typical daily time profiles of diabetic BG and ISFG into a single graph and ask people to visually estimate the average time offset, numbers as high as 1 hour would occur commonly, and 2 hours occasionally. Medical doctors are primarily interested in BG and not in ISFG because today's invasive methods measure BG. The bottom line is that in diabetics, ISFG does not track BG closely enough to allow any of today's noninvasive methods to achieve full clinical usefulness and to successfully pass comparisons with invasive methods.
The fact that many of today's NIR absorbance-based optical method
Lateef Marvin M.
Lin Jeoyuh
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