Method and apparatus for biological fluid analyte concentration measurement using generalized distance outlier detection
First Claim
1. An improved method for forming a calibration model for use in determining concentration of an analyte of a biological fluid of a mammal, comprising the steps of:
- collecting a set of calibration samples from a plurality of sources of the biological fluid;
generating near-infrared electromagnetic radiation having a plurality of wavelengths;
irradiating each of the calibration samples with the radiation so that a portion of the radiation at each of the wavelengths is transmitted through each of the calibration samples;
measuring intensity of the radiation transmitted through each of the calibration samples at each of the wavelengths thereby forming a set of calibration data;
processing the set of calibration data, including forming the set of calibration data into a n×
p matrix defining a space, wherein n is the number of calibration samples and p is the number of wavelengths at which intensity of transmitted radiation is measured, forming a subspace of the space wherein sources of relatively greater variations within the set of calibration data are represented, projecting the set of calibration data into the subspace, determining a generalized distance within the subspace between each calibration sample and a centroid of a distribution formed by the set of calibration samples, identifying calibration outliers as those calibration samples having a generalized distance greater than a preselected magnitude, forming a reduced set of calibration samples from calibration samples remaining after removal of calibration outliers; and
constructing a calibration model from the reduced set of calibration samples to predict concentration of the analyte in an unknown sample of the biological fluid.
4 Assignments
0 Petitions
Accused Products
Abstract
A method and apparatus for measuring the concentration of an analyte present in a biological fluid is disclosed. The method includes the steps of applying NIR radiation to calibration samples to produce calibration data, analyzing the calibration data to identify and remove outliers, constructing a calibration model, collecting and analyzing unknown samples to identify and remove outliers, and predicting analyte concentration of non-outliers from the calibration model. Analysis of the calibration data includes data pretreatment, data decomposition to remove redundant data, and identification and removal of outliers using generalized distances. The calibration model may utilize principal component regression, partial least squares, multiple linear regression, or artificial neural networks, and reduction using principal component analysis or partial least squares scores. Unknown sample data is analyzed using data pretreatment followed by projection into the calibration model space, and identification and removal of outliers, with prediction of analyte concentration using the calibration model. The apparatus includes a pump which circulates a sample through tubing to fill a flowcell. Light from a NIR source is synchronized with a detector, facilitating light and dark measurements, and passes through a monochrometer and the flowcell and strikes the detector, whereby radiation transmitted through the sample is measured. Measurement data is stored in a general purpose programmable computer also controlling the pump, the detector, synchronization, and the monochrometer. The computer includes a general purpose microprocessor configured with computer program code employing the steps of the method.
260 Citations
42 Claims
-
1. An improved method for forming a calibration model for use in determining concentration of an analyte of a biological fluid of a mammal, comprising the steps of:
-
collecting a set of calibration samples from a plurality of sources of the biological fluid; generating near-infrared electromagnetic radiation having a plurality of wavelengths; irradiating each of the calibration samples with the radiation so that a portion of the radiation at each of the wavelengths is transmitted through each of the calibration samples; measuring intensity of the radiation transmitted through each of the calibration samples at each of the wavelengths thereby forming a set of calibration data; processing the set of calibration data, including forming the set of calibration data into a n×
p matrix defining a space, wherein n is the number of calibration samples and p is the number of wavelengths at which intensity of transmitted radiation is measured, forming a subspace of the space wherein sources of relatively greater variations within the set of calibration data are represented, projecting the set of calibration data into the subspace, determining a generalized distance within the subspace between each calibration sample and a centroid of a distribution formed by the set of calibration samples, identifying calibration outliers as those calibration samples having a generalized distance greater than a preselected magnitude, forming a reduced set of calibration samples from calibration samples remaining after removal of calibration outliers; andconstructing a calibration model from the reduced set of calibration samples to predict concentration of the analyte in an unknown sample of the biological fluid. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 24, 25, 26, 27, 28)
-
-
11. An improved method for determining concentration of an analyte of a biological fluid of a mammal, comprising the steps of:
-
collecting a set of calibration samples from a plurality of sources of the biological fluid and an unknown sample from an unknown source of the biological fluid; generating near-infrared electromagnetic radiation having a plurality of wavelengths; irradiating each of the calibration samples and the unknown sample with the radiation so that a portion of the radiation at each of the wavelengths is transmitted through each of the calibration samples and the unknown sample; measuring intensity of the radiation transmitted through each of the calibration samples at each of the wavelengths thereby forming a set of calibration data and through the unknown sample at each of the wavelengths thereby forming a set of sample data; processing the set of calibration data, including forming the set of calibration data into a n×
p matrix defining a space, wherein n is the number of calibration samples and p is the number of wavelengths at which intensity of transmitted radiation is measured, forming a subspace of the space wherein sources of relatively greater variations within the set of calibration data are represented, projecting the set of calibration data into the subspace, determining a generalized distance within the subspace between each calibration sample and a centroid of a distribution formed by the set of calibration samples, identifying calibration outliers as those calibration samples having a generalized distance greater than a preselected magnitude, forming a reduced set of calibration samples from calibration samples remaining after removal of calibration outliers;constructing a calibration model from the reduced set of calibration samples to predict concentration of the analyte in the unknown sample; and applying the calibration model to the set of sample data including projecting the set of sample data into the space defined by the model, determining a generalized distance for the unknown sample according to the model, identifying the unknown sample as a sample outlier provided the generalized distance of the unknown sample is greater than the preselected magnitude, and predicting concentration of the analyte in the unknown sample according to the model provided the generalized distance of the unknown sample is not greater than the preselected magnitude. - View Dependent Claims (12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 29, 30)
-
-
31. Apparatus for determining concentration of an analyte in an unknown sample of a biological fluid of a mammal comprising:
-
a positioner unit capable of sequentially positioning the unknown sample and each of a set of calibration samples of the biological fluid collected from a plurality of sources; a radiation emitter capable of emitting near-infrared electromagnetic radiation at a preselected plurality of wavelengths, said radiation emitter positioned to sequentially direct radiation of each of the wavelengths into and partially through each of the calibration samples and the unknown sample; a near-infrared electromagnetic radiation detector disposed to sequentially receive and measure intensity of the radiation transmitted through each of the calibration samples at each of the wavelengths to form a set of calibration data and through the unknown sample to form a set of sample data; and a computer connected to said detector and having a general purpose microprocessor configured with computer program code to form the set of calibration data into a matrix defining a space, form a subspace of the space wherein sources of relatively greater variations within the set of calibration data are represented, project the set of calibration data into the subspace, determine a generalized distance within the subspace between each calibration sample and a centroid defined by a distribution formed by the set of calibration samples, identify calibration outliers as those calibration samples having a generalized distance greater than a preselected magnitude, form a reduced set of calibration samples from calibration samples remaining after removal of calibration outliers, construct a calibration model from the reduced set of calibration samples to predict concentration of the analyte in the unknown sample, project the set of sample data into a space defined by the model, determine a generalized distance for the unknown sample according to the model, identify the unknown sample as a sample outlier provided the generalized distance of the unknown sample is greater than the preselected magnitude, and predict concentration of the analyte in the unknown sample according to the model provided the generalized distance of the unknown sample is not greater than the preselected magnitude. - View Dependent Claims (32, 33, 34, 35, 36, 40, 41, 42)
-
-
37. Apparatus for determining concentration of an analyte in an unknown sample of a biological fluid of a mammal comprising:
-
a positioner unit capable of sequentially positioning the unknown sample and each of a set of calibration samples of the biological fluid collected from a plurality of sources, including a flowcell having an input orifice and an output orifice, and a pump disposed in fluid connection between said input orifice and said output orifice whereby each of the set of calibration samples and the unknown sample may be sequentially circulated through said flowcell; a radiation emitter capable of emitting near-infrared electromagnetic radiation at a preselected plurality of wavelengths, said radiation emitter positioned to sequentially direct the radiation of each of the wavelengths into and partially through each of the calibration samples and the unknown sample; a near-infrared electromagnetic radiation detector disposed to sequentially receive and measure intensity of the radiation transmitted through each of the calibration samples at each of the wavelengths to form a set of calibration data and through the unknown sample to form a set of sample data; a temperature controller capable of controlling temperature of said positioner unit and said detector; a noise reducer coupled to said radiation emitter and said detector, and capable of reducing noise in measurements of intensity of that portion of the radiation transmitted through each of the calibration samples and the unknown sample; and a computer connected to said detector and having a general purpose microprocessor configured with computer program code to form the set of calibration data into a matrix defining a space, form a subspace of the space wherein sources of relatively greater variations within the set of calibration data are represented, project the set of calibration data into the subspace, determine a generalized distance within the subspace between each calibration sample and a centroid defined by a distribution formed by the set of calibration samples, identify calibration outliers as those calibration samples having a generalized distance greater than a preselected magnitude, form a reduced set of calibration samples from calibration samples remaining after removal of calibration outliers, construct a calibration model from the reduced set of calibration samples to predict concentration of the analyte in the unknown sample, project the set of sample data into a space defined by the model, determine a generalized distance for the unknown sample according to the model, identify the unknown sample as a sample outlier provided the generalized distance of the unknown sample is greater than the preselected magnitude, and predict concentration of the analyte in the unknown sample according to the model provided the generalized distance of the unknown sample is not greater than the preselected magnitude. - View Dependent Claims (38, 39)
-
Specification