human blood includes a plurality of test constituents present in unknown concentrations together with at least one reference constituent present in a known concentration . because the concentration of water in blood is both known and nearly invariant across the human population and time , it is convenient to use water as the reference constituent . however , the methods described below can be applied to any constituent which is present at a known concentration . the method has the steps of providing an illumination source that generates illumination radiation to a measurement site across a portion of the spectrum that contains absorbance bands of said substance of interest . the measurement site is illuminated with said illuminating radiation and radiation transmitted , transflected , or reflected from said measurement site is detected by a detector array . in the preferred embodiment , the detector array has a plurality of detectors having distinct maximum spectral response characteristics in different regions of said portion of the spectrum used for illumination . in one embodiment , the plurality of detectors includes at least a first detector and a second detector having spectral characteristics with greater responsiveness to the absorbance bands of water than to the other constituents in the blood . each of the detectors in said detector array provides an output signal indicative of the amount of radiation it receives in a selected time period . the method also contains the step of determining a differential value of the output signals for periods of arterial pulsation by comparing values obtained during systolic portions of the arterial pulse with values obtained during a diastolic portions of said pulse . the method of comparing predominantly water - responsive channels to predominantly non - water - responsive channels is effective if good wavelength separation can be achieved . for example , oxyhemoglobin ( and deoxyhemoglobin ) are dominate absorbers in the 600 - 1100 nm range , while water is the dominant absorber in the wavelength range greater than 1100 nm . accordingly , the ratio method may be used if hemoglobin concentration is sought . however , this is not effective for glucose which has its primary absorbance in the greater than 1100 nm range . accordingly , another method of using water as a universal standard is needed to eliminate the pathlength variability and other interference problems . in the case where water is a dominant absorbing constituent in all the detection channels required for measurement of a constituent of interest , then a method is required that represents the constancy of the water concentration of the arterial blood over sets of detection channels employed in the measurement . this representation can be achieved by the consideration of a set of the detection channels as the elements of a vector . the output of n detectors can be used to generate a vector in an n - dimensional space . for example , a vector b can be measured in vivo which represents the set of fractional modulations in each detection channel by the cardiac pulse caused by all the absorbing constituents in the blood . similarly , a vector g , denoting absorptivity of glucose or any other constituent of interest , may be generated from the in vitro absorptivities of said constituent as measured in each of the n detection channels ; each additional absorbing constituent has its own , unique vector . the underlying assumptions in the disclosed method are that the relative magnitude and direction of the vector of the analyte of interest and the vector of water from the detectors in the n - dimensional space will maintain substantially the same relative directions and magnitudes as they have in vitro . based on these assumptions , an in vitro measurement of water can be taken using the same detector configuration employed for in vivo measurements , and a water vector , w , representing the in vitro water results in the same n - dimensional space , can be determined . by definition , the vector w is deemed to be a unit vector . the dot product of b and w , b · w , is a scalar which can then be used to normalize the vector b . normalization is achieved by the formula b / b · w yielding a vector b which has the same direction as b but with two desirable properties . first , if the only reason for changes in b is variations in pathlength due to changes in blood pressure or other changes in pulse magnitude , the magnitude and direction of b , computed by this method , will not vary . second , the component of b in the water direction will be the unit vector w ; the component of b in the water direction is b · w , resulting in b · w / b · w = 1 , i . e ., the unit vector in the water direction , w . the first property achieves the goal of eliminating dependency on pathlength changes , while the second provides universality of calibration related to the constancy of water content in blood . this self normalization allows information from all the detection channels to be used in the measurement of b , unlike the prior art reference measurements . one may also use another constituent , g , and perform similar operations as with b to express the response to all the constituents of interest on the same water - normalized scale . once this has been done , changes in the direction of b toward the vector g representing any constituent of interest may be clearly seen to be indicative of increases in the concentration of that constituent . furthermore , the normalization of all the vectors to the approximately known concentration of water , in the context of the assumption of constant relative directions and magnitudes of all the vectors so normalized , permits the calculation of the magnitude of the concentration change causing such a shift in vector b . fig1 shows an optical system useful for practicing the present method . this optical system employs collimating optics for both illumination and detection , with the detector having a plurality of detector units placed such that they achieve congruent sampling . radiation source 10 is selected so that it provides broad spectrum illumination , e . g ., 700 - 2500 nm illumination . radiation from radiation source 10 passes through collimating lens 12 before striking tissue 20 . optional aperture 14 is shown which helps define the collimation optics in conjunction with collimating lens 12 . once the radiation has traversed tissue sample 20 and exits the tissue through area defining aperture 25 , it passes through detector collimating optics 30 formed of converging lens 32 , aperture 34 and recollimating lens 36 . this type of collimating optics is conventionally used in telescopes and other devices where collimation of light is desired . the collimated beam exiting collimation optics 30 , specifically recollimating lens 36 , then goes through a series of beam splitters 42 a , 42 b and 42 c and onto four detector units 44 a , 44 b , 44 c and 44 d . the beam splitters and detector units are arranged such that the entire detection unit 40 provides congruent sampling of the beam . more particularly , the beam splitters and detector units are arranged such that the pathlength and angles from recollimating lens 36 to any of detector units 44 are equal and each of detector units 44 are optically superimposable upon the other . if the analyte of interest has spectral characteristics which can be differentiated from those of water , at least two of detector units 44 should have spectral characteristics with greater responsiveness to the absorbance bands of water than to the other constituents of the blood . although four detector units are shown , the exact number may be varied . in operation , radiation i 01 from the broadband source 10 penetrates the finger 20 where it interacts with the various constituents in the blood and the tissue . as a result of the heartbeat and the resulting pulsatile blood flow , this interaction is a time - varying phenomenon . during the diastolic phase of the heartbeat , as shown in fig2 a , the incident radiation interacts with the tissue 201 d , the venous blood 202 d , and the arterial blood 203 d of the finger 20 d . during the systolic phase , shown in fig2 b , the amount of tissue 201 s and venous blood 202 s in the finger 20 s is approximately the same as that which was present in the diastolic phase . however , the amount of arterial blood 203 s has increased . as a result , the output radiation i sλ during the systolic phase differs from the output radiation i dλ during the diastolic phase to the extent that the extra blood volume results in additional absorption . fig . 3 shows a different apparatus for use in practicing the present invention . fig3 shows a system using the beam splitter array of fig1 reversed for congruent illumination rather than congruent sampling . four radiation sources 310 a , 310 b , 310 c and 310 d , are used to illuminate the tissue sample . the radiation issuing from each of the radiation sources goes through a collimating lens ( 312 a , 312 b , 312 c and 312 d , respectively ) and then is redirected by one of the beam splitters 316 a , 316 b or 316 c to illuminate tissue 320 . the radiation transmitted by tissue 320 passes through converging lens 332 and aperture 334 before striking detector 344 . optionally , an additional lens 336 ( not shown ) could be used to recollimate the transmitted radiation before it strikes detector 344 . the radiation sources , collimating lenses and beam splitters are arranged to provide congruent illumination and each separate radiation source may have an associated modulator to provide a different modulation to the radiation issuing from that radiation source . this type of modulation apparatus , and its advantages , is described in more detail in u . s . pat . no . 5 , 424 , 545 . briefly , using a plurality of modulators , each providing a different modulation to the associated radiation issuing therefrom , and using a form of modulation differentiation at the detector ( such as electronically separating the signals based on modulation frequency ) provides a method which allows differentiation at the detector of the source of the illuminating radiation , and accordingly allows additional information to be generated from a single detector . for example , if the radiation sources cover different wavelengths , a single detector can differentiate the intensity of the transmitted radiation at each wavelength range by using the modulation to determine the wavelength range . this can eliminate the requirement of the system illustrated above which requires a plurality of detector units . for improved results , both the congruent illumination shown in fig3 and the congruent sampling shown in fig1 may be used in the same device . similarly , a filter wheel that provides different wavelength transmission can be used on either the illumination or detection side of the device . it is also possible to use fiber optics to transmit light on either the illumination or detector side of the apparatus . fig4 shows a plot of predicted hemoglobin concentration , made using the first embodiment of the in vivo , noninvasive methods and apparatus described herein , with actual hemoglobin as measured using a blood sample . the actual hemoglobin reading is determined using capillary blood sample on a hemocue b - hemoglobin analyzer ( mission viejo , calif .) for 10 samples . the predicted values are determined using an apparatus such as is shown in fig1 in a transmission mode with a fiber optic input placed next to a fingernail and the detector on the opposite side of the finger . four congruent ingaas detectors are used , with filters whose maximal transmission is located near 1064 nm , 1200 nm , 1300 nm , and 1625 nm before the individual detectors . the 1200 nm and 1300 nm filters are the water channels . the illumination source is a 2 . 7 w halogen light source with the fiber optic output focused on elevated fingernails . the elevation of the finger above the heart also appears to improve accuracy . optical transmission data from each detector channel is digitized by hp3458a multimeters and transmitted to a pentium pc via labview software for post - processing to derive pulsatile modulation values by matlab software . each data run consists of thirty seconds of raw data , or about 30 cardiac pulses at normal cardiac rates . the data from each run was used in a ratio calculation , with all four possible hemoglobin to water detection channel ratios being used to generate the results . the linear regression analysis is shown in fig4 . the standard error of calibration was 0 . 24 g hb / dl , on values ranging from 13 - 19 g hb / dl . the advantages of the present invention apply to spectrophotometric systems such as those employed in pulse oximetry . while the shot - noise constraints on the detected intensity are lower because the absorption of the hemoglobins are so much larger the acceptance angle restrictions provide greater linearity and improved calibratability , as well as reduction in the severity of motion and breathing artifacts , and other limitations on universality of calibration . for the analysis of trace constituents where the high photon flux requirement is critical , the present invention is particularly advantageous when combined with the use of broadband and broadband overlapping detectors , as taught in the block ′ 265 patent and the parent applications . the foregoing description is meant to be explanatory only and is not intended to be limiting as to the scope of the invention . the invention is defined by the following claims .
the absence of a defined optical pathlength for in vivo measurements creates problems for the noninvasive measurement of analyte concentration . these problems can be reduced by combining measurements made at several wavelengths and using the fact that normal renal function causes the concentration of water in whole blood to be tightly controlled . hence , the concentration of water in arterial blood can serve as a useful internal standard for such measurements . the measurements are then procured so as to remove the dependency of concentration on path length traversed by the illuminating radiation and on the scattering properties of the volume through which the illuminating radiation propagates . using this method , one can create improved calibration for measurements of absorbing constituents in arterial blood and thereby provide absolute concentration measurements of constituents such as hemoglobin and glucose in arterial blood .