CN1938589B - Method and apparatus for implementing threshold based correction functions for biosensors - Google Patents

Abstract

A biosensor system, method and apparatus are provided for implementing threshold based correction functions for biosensors. A primary measurement of an analyte value is obtained. A secondary measurement of a secondary effect is obtained and is compared with a threshold value. A correction function is identified responsive to the compared values. The correction function is applied to the primary measurement of the analyte value to provide a corrected analyte value. The correction method uses correction curves that are provided to correct for an interference effect. The correction curves can be linear or non-linear. The corrction method provides different correction functions above and below the threshold value. The correction functions may be dependent or independent of the primary measurement that is being corrected. The correction functions may be either linear or nonlinear.

Description

Method and apparatus for implementing a threshold-based correction function for a biosensor

technical field

The present invention relates generally to biosensors and, more particularly, to a method and apparatus for implementing a threshold-based correction function for a biosensor.

Background technique

Quantitative determination of analytes in body fluids is important in the diagnosis and management of certain physiological abnormalities. For example lactate, cholesterol, bilirubin need to be monitored in certain individuals. In particular, the measurement of glucose in body fluids is important for diabetic individuals who need to frequently check their glucose levels in body fluids to regulate their dietary glucose intake. While the remainder of this disclosure will be directed to the determination of glucose, it should be understood that the procedures and devices of the present invention can be used to measure other analytes upon selection of an appropriate enzyme. Ideal diagnostic equipment for the detection of glucose in fluids should be simple and should not require a high level of skill on the part of the technicians performing the assay. In many cases, these assays are performed by the patient, thus increasing the need for assays that are easy to perform. Furthermore, such devices should be based on ingredients that are stable enough for long-term storage.

A method for determining the concentration of an analyte in a fluid may be based on an electrochemical reaction between an enzyme and an analyte specific for the enzyme and a mediator that maintains the enzyme in its original oxidized state. Suitable oxidoreductases include: oxidases, dehydrogenases, catalases and peroxidases. For example, when glucose is the analyte, the reaction between glucose oxidase and oxygen is represented by equation (A).

(A)

In a colorimetric test, the release of hydrogen peroxide in the presence of peroxidase results in a change in the color of the redox indicator, where the color change is proportional to the level of glucose in the test fluid. Although colorimetric assays are performed semi-quantitatively by using a color table to compare the color change of a redox indicator to that obtained with a test fluid of known glucose concentration, and can be read by spectrophotometric equipment to When colorimetric assays are performed at higher levels of quantification, the results are generally neither as precise nor as rapid as those obtained with electrochemical biosensors. As used herein, the term "biosensor system" refers to an analytical device that selectively responds to an analyte in an appropriate sample, converting its concentration into an electrical signal, through biorecognition signals and physico-chemical transduction It is realized by a combination of transducers.

H ₂ O ₂ →O ₂ +2H ⁺ +2e ^-

(B)

The current is then converted into an electrical signal that is directly related to glucose concentration.

In the initial step of the reaction represented by equation (A), glucose present in the test sample converts the oxidized flavin adenine dinucleotide (FAD) center of the enzyme to its reduced form ( _FADH2 ). Because these redox centers are essentially electrically insulating in the enzyme molecule, any direct transfer to the surface of conventional electrodes does not occur to measurable levels in the absence of unacceptably high voltages. electron transfer. Modifications to this system include the use of non-physiological redox coupling between the electrode and the enzyme to shuttle electrons between ( _FADH2 ) and the electrode. This is represented by the following scheme, where a redox coupler (typically, called a mediator) is represented by M:

Glucose+GO(FAD)→Glucolactone+GO(FADH ₂ )

GO(FADH ₂ )+2M _OX →GO(FAD)+2M _red +2H ⁺

2M _red → 2M _O× +2e ^- (on electrodes)

In this scheme, GO(FAD) represents the oxidized form of glucose oxidase and GO(FADH ₂ ) represents its reduced form. The mediator substance M _red shuttles electrons from the reduced enzyme to the electrode, thereby oxidizing the enzyme, leading to its regeneration in situ, which is of course desirable for economical reasons. The main purpose of using a medium is to lower the operating potential of the sensor. An ideal medium would be redoxed at the electrodes at low potentials where impurities in the chemical layer and interfering species in the sample would not be oxidized, thereby minimizing interference.

Because of the ability to accept electrons from the reduced enzyme and transfer them to the electrode, a wide variety of compounds can be used as mediators. Mediators known to be useful as electron transfer reagents in analytical assays are substituted benzoquinones or naphthoquinones disclosed in US Patent 4,746,607; N-oxides, nitroso compounds, hydroxylamines and oxines, specifically Flavins, phenazines, phenothiazines, indophenols, substituted 1,4-benzoquinones and indamines disclosed in EP 0 354 441; and phenazines described in US Patent 3,791,988 Azinium/phenoxazinium salts. For a review of electrochemical mediators in biological redox systems, see Analytica Clinica Acta. 140 (1982), Pp 1-18.

A better known agent is hexacyanoferrate, also known as ferricyanide, found in Discussed in et al., Clinica Chimica Acta ., 57 (1974), pp. 283-289. US Patent No. 4,929,545 discloses the use of a combination of a soluble ferricyanide compound and a soluble iron-containing compound in a composition for the determination of an analyte in a sample by an enzyme. Substituting the iron salt of ferricyanide for the oxygen in equation (A) provides the following equation:

Ferricyanide is reduced to ferrocyanide by accepting electrons from glucose oxidase.

Another way to express this reaction can be represented by the following equation C

Glucose + GO _X(OX) → Glucolactone + GO _X(red)

GO _X(red) +2Fe(CN ₃ ) ^3- ₆ →GO _X(OX) +2Fe(CN) ^4- +2e ^-

(C)

The released electrons are directly equivalent to the amount of glucose in the fluid to be measured, and can be correlated to the amount of glucose by measuring the current generated in the fluid by applying a voltage to the fluid. Oxidation of ferrocyanide at the anode renews the cycle.

U.S. Patent 6,391,645 to Huang et al., issued May 21, 2002, assigned to the present assignee, discloses a method and apparatus for correcting for the effect of ambient temperature in a biosensor. It measures the value of the ambient temperature. The sample is applied to the biosensor and the electrical current generated in the sample to be tested is measured. Values for the observed analyte concentrations were calculated from the currents by standard response curves. The measured ambient temperature value is then used to correct the observed analyte concentration, thereby increasing the accuracy of the analyte determination. The concentration of the analyte can be calculated by solving the following equation:

G2＝(G1-(T ₂ ² -24 ² )*12-(T ₂ -24)*11)/

((T ₂ ² -24 ² )*S2+(T ₂ -24)*S1+1)

Wherein, G1 is the observed concentration value of the analyte, _T2 is the measured ambient temperature value, and I1, I2, S1 and S2 are preset parameters.

While the method and apparatus of U.S. Patent 6,391,645 provide improvements in the accuracy of determining analytes, there remains a need for improved calibration mechanisms that can be used in any system that measures analyte concentrations.

The term "biosensor" as used in the following specification and claims refers to an electrochemical sensor strip (strip) or sensor assembly of an analytical device or a biosensor system that is capable of making selectivity for an analyte in an appropriate sample response and convert its concentration into an electrical signal. Biosensors generate electrical signals directly, which simplifies instrument design. In addition, biosensors offer the advantage of low material costs because only thin layers of chemicals are deposited on the electrodes, with little wasted material.

The term "sample" is defined as a composition containing an unknown amount of an analyte of interest. Typically, samples for electrochemical analysis are in liquid form, preferably, the sample is an aqueous mixture. The sample can be a biological sample, eg blood, urine or saliva. A sample can be a derivative of a biological sample, eg, an extract, dilution, filtrate, or reconstituted precipitate.

The term "analyte" is defined as a substance in a sample, the presence or amount of which is to be determined. During analysis, the analyte interacts with the oxidoreductase present, which may be a substrate of the oxidoreductase, a coenzyme, or another substance that affects the interaction between the oxidoreductase and its substrate.

Contents of the invention

An important aspect of the present invention is to provide a new and improved biosensor system for determining the presence or amount of a substance in a sample, which includes a method and apparatus for implementing threshold-based correction function.

Briefly, the present invention provides a method and apparatus for implementing a threshold-based correction function for a biosensor. The sample is applied to the biosensor to obtain a primary measurement of the analyte to be analyte. A secondary measure of impact on the secondary is obtained and compared to a threshold. Determine the correction function that responds to the values being compared. Applying the correction function to the primary measurement of the analyte provides a corrected analyte value.

According to a feature of the invention, the correction method uses a correction curve, which is provided to correct for disturbing effects. Calibration curves can be linear or non-linear. The correction method provides different correction functions above and below the threshold. The correction function may or may not be dependent on the primary measurement being corrected. Correction functions can be linear or non-linear.

According to a feature of the invention, the secondary measure of secondary influences includes a large number of influences which can be used individually or combined together to determine the correction function. For example, secondary effects including temperature, hemoglobin, and hematocrit concentration of blood samples were determined and used to minimize the interference of secondary effects on the accuracy of reported results.

Description of drawings

The present invention, having the above and other objects and advantages, is best understood from the following detailed description of the preferred embodiments of the invention illustrated in the accompanying drawings, in which:

Fig. 1 is a schematic structural diagram of a biosensing system according to the present invention;

FIG. 2 is a flow chart illustrating exemplary logical steps performed in accordance with the present invention for implementing a threshold-based method of correcting for secondary effects, such as correcting for the environment in the biosensor system of FIG. 1 the effect of temperature; and

Figures 3 and 4 are exemplary stored calibration curves illustrating calibration features according to the present invention.

Detailed ways

Referring now to the drawings, Figure 1 shows a schematic block diagram of a biosensor system, generally designated by the reference numeral 100, arranged in accordance with the principles of the present invention. The biosensor system 100 comprises a microprocessor 102 to which is connected a memory 104 for storing program and user data as well as a calibration curve for implementing the threshold-based correction for secondary influences according to the invention. A meter function 106 is coupled to a biosensor 108, which is operatively controlled by the microprocessor 102, for recording assay values, such as blood glucose assay values. An on/off input on lead 110 , responsive to a user's on/off input, is coupled to microprocessor 102 for running the blood test sequence mode of biosensor system 100 . A system feature input on lead 112 , responsive to user input, is coupled to microprocessor 102 for selectively operating a system feature mode of biosensor 100 . A thermistor 114 shown on lead 116 provides a temperature signal input that is coupled to the microprocessor 102 for detecting disturbing effects, eg, temperature information for the sensor 108 in accordance with the present invention. A signal input shown on lead 120 is coupled to microprocessor 102 for a second measurement of an interfering substance such as hemoglobin, optionally provided by meter function 106 .

A display 130 is coupled to the microprocessor 102 for displaying information to the user, including test results. A battery monitoring function 132 is coupled to the microprocessor 102 for detecting a low or no battery condition. A warning function 134 is coupled to the microprocessor 102 for detecting predetermined system conditions and for generating warning indications to a user of the biosensor system 100 . A data port or communication interface 136 is also provided for coupling data to and from an attached computer (not shown). Microprocessor 102 contains suitable programming for running the method of the present invention, as shown in FIG. 2 .

Biosensor system 100 is shown in simplified form, but sufficient to understand the invention. The illustrated biosensor system 100 is not intended to imply structural or functional limitations. The invention can be used with a variety of hardware implementation tools and systems.

According to the present invention, the biosensor 100 operates a preferred embodiment calibration method, eg, reducing temperature deviation, which has a general form as shown in Table 1 below, and as illustrated and described in FIG. 2 . The present invention provides an algorithmic correction method that advantageously improves the accuracy of diagnostic chemistry assays by correcting for secondary effects, such as interfering substances or temperature effects.

It should be understood that the present invention can be used in any system, electrochemical or optical, that measures the analyte concentration as a primary measurement and then uses a secondary measurement of interfering substances (e.g., hemoglobin) or interfering influences (e.g., temperature). Secondary measurements are used to compensate for secondary effects and improve the accuracy of reported results.

It is also desirable to minimize interference from volume fraction or hematocrit of red blood cells on the accuracy of reported results. The conductivity or impedance of whole blood depends on the concentration of hematocrit. The meter function 120 can be used to measure the resistance of the sample fluid on the signal input line 120, and the measured value can advantageously be used to correct for the effect of hematocrit on the reported results. For example, the measured electrical resistance can advantageously be used to estimate the hematocrit concentration of a blood sample, which is then used to correct the measurement for hematocrit effects to determine the concentration of a substance of interest in the blood. The present invention provides an algorithmic correction method that advantageously improves the accuracy of diagnostic chemistry assays by correcting for secondary effects including interference from hematocrit and temperature Influence.

According to the invention, the algorithmic correction method uses a correction curve, eg as illustrated and described in Figures 3 and 4, which can be adapted to correct for any well-established interference effects. Calibration curves can be linear or non-linear. The algorithmic correction method has the feature that it can be corrected by changing only the coefficients of the equations as described below. First, different correction functions above and below a threshold can be provided. Second, the correction function may or may not depend on the primary measurements to be corrected. Third, the function used for correction can be linear or non-linear.

Table 1: General correction algorithm table

Step 1. Obtain primary measurements (Gn).

Step 2. Obtain secondary measurements for correcting Gn(T)

Step 3A If T≤Tc, then:

1. A=f(Gn)

2. _Cn = F*T+A*(Tc-T)+H

Step 3B If T>Tc, then:

3. I＝f ₂ (G _N )

4. _Cn = F*T+I*(T-Tc)+H

5.G _c ＝(G _N /G _n )

in:

_Gn = uncorrected analyte concentration measurement;

T = secondary measurement used to correct the primary measurement;

_Tc = decision point or threshold, above or below which secondary measurements may advantageously use different correction functions;

G _c = final calibration result; and

A, I, F, H are coefficients that control the magnitude of the calibration line or define the calibration curve.

Referring now to FIG. 2 , which illustrates exemplary logical steps performed in accordance with the present invention, which are steps for implementing a threshold-based method of correcting for secondary effects, such as the effect of ambient temperature in a biosensor system 100 . Insert the strip as shown at block 200 and then wait until the sample run to be applied is shown at block 202 . As represented by block 204, a primary measurement Gn is obtained. Then, as represented by block 206, a secondary measurement T for correcting Gn(T) is obtained. The secondary measurement T is then compared to a threshold Tc, as indicated by decision block 208 . If the secondary measurement T is less than or equal to the threshold Tc, then as shown in block 210, a coefficient A for controlling the correction magnitude is determined, where A=f(Gn). Then, as shown in block 210, a correction value Cn is calculated, where Cn=F*T+A*(Tc-T)+H. Conversely, if the secondary measured value T is higher than the threshold Tc, then as shown in block 214, a coefficient I for controlling the magnitude of the correction is determined, where I=f2(Gn). The correction value Cn is then calculated as shown in block 216, where Cn=F*T+I*(T-Tc)+H. As shown in block 218 , the final correction result Gc is calculated, where Gc=Gn/Cn, to complete the correction algorithm, as shown in block 220 .

Referring now to FIGS. 3 and 4 , there are shown first and second examples, generally designated by the reference numerals 300 and 400 , respectively, in which exemplary theoretical lines of correction are shown. In Figures 3 and 4, the percentage (%) correction is shown on the vertical axis and the secondary measured value T is shown on the horizontal axis. The threshold Tc is represented by the line labeled Tc.

Figure 3 shows the isometric correction for different primary measurement concentrations Gn, where the correction value is dependent on the primary measurement concentration Gn. As shown in example 300 in FIG. 3, the magnitude of the correction value Cn varies with the analyte concentration Gn when the secondary measurement T is above or below the threshold Tc. Figure 4 shows the isovolumic correction lines at different primary measured concentrations Gn, where, above the threshold Tc, the correction value depends on the primary measured concentration Gn, while below or equal to the threshold Tc, the correction value Constant or independent of the primary measured concentration Gn.

The invention has been described with reference to details of its embodiment shown in the drawings, these details not being intended to limit the scope of the invention as shown in the appended claims.

Claims (21)

1. method, be used to realize to be used for biology sensor, based on the correction function of threshold value, described method comprises following action:

Sample application to biology sensor, is obtained to treat the primary measurement values of analyte value;

Acquisition is to the secondary measured value of secondary influence;

Described secondary measured value and threshold with described secondary influence;

Respond to the described value that is compared, use at least one coefficient value to determine correction function, described at least one coefficient value depends on the described primary measurement values of described analysans value; And

The correction function that described warp is determined is applied to described primary measurement values, so that the analysans value through overcorrect to be provided.

2. the method for claim 1, be used to realize to be used for biology sensor, based on the correction function of threshold value, wherein, describedly respond to the described value that is compared and determine that the action of correction function comprises following action: the described secondary measured value of determining described secondary influence is less than or equal to described threshold value, determine the first coefficient A, the described first coefficient A is used to control the amplitude of described correction function.

3. method as claimed in claim 2, be used to realize to be used for biology sensor, based on the correction function of threshold value, it also comprises following action: calculate the described correction function by following formula representative:

C _n＝F＊T+A＊(T _c-T)+H

Wherein, T represents the described secondary measured value of described secondary influence, and Tc represents described threshold value, and F, H are predefined coefficients.

4. method as claimed in claim 3, be used to realize to be used for biology sensor, based on the correction function of threshold value, wherein, described definite correction function is applied to described primary measurement values and also comprises following action: calculate described analysans value through overcorrect by following formula representative so that the action through the analysans value of overcorrect to be provided

Gc＝Gn/Cn

Wherein, Gn represents the described primary measurement values of described analysans value.

5. the method for claim 1, be used to realize to be used for biology sensor, based on the correction function of threshold value, wherein, describedly respond to the described value that is compared and determine that the action of correction function comprises following action: the described secondary measured value of determining described secondary influence is greater than described threshold value, determine coefficient I, described coefficient I is used to control the amplitude of described correction function.

6. method as claimed in claim 5, be used to realize to be used for biology sensor, based on the correction function of threshold value, it also comprises following action: calculate the described correction function by following formula representative

C _n＝F＊T+I＊(T-T _c)+H

Wherein, T represents the described secondary measured value of described secondary influence, T _cRepresent described threshold value, F, H are predefined coefficients.

7. method as claimed in claim 6, be used to realize to be used for biology sensor, based on the correction function of threshold value, wherein, described definite correction function is applied to described primary measurement values and also comprises following action: calculate described analysans value through overcorrect by following formula representative so that the action through the analysans value of overcorrect to be provided

Gc＝Gn/Cn

Wherein, Gn represents the described primary measurement values of described analysans value.

8. the method for claim 1, be used to realize to be used for biology sensor, based on the correction function of threshold value, wherein, describedly respond to the described value that is compared and determine that the action of correction function comprises following action: store predefined calibration curve, described predefined calibration curve is provided to proofread and correct disturbing effect.

9. the method for claim 1, be used to realize to be used for biology sensor, based on the correction function of threshold value, wherein, describedly respond to the described value that is compared and determine that the action of correction function comprises following action: the described secondary measured value that responds to the described secondary influence that is less than or equal to described threshold value, determine the first coefficient A, and definite response is in the described correction function of the described definite first coefficient A.

10. method as claimed in claim 9, be used to realize to be used for biology sensor, based on the correction function of threshold value, wherein, describedly respond to the described value that is compared and determine that the action of correction function comprises following action: respond to described secondary measured value greater than the described secondary influence of described threshold value, determine the second coefficient I, and definite response is in the described correction function of the described definite second coefficient I.

11. method as claimed in claim 10, be used to realize to be used for biology sensor, based on the correction function of threshold value, wherein, determine the described first coefficient A and determine that the action of the second coefficient I comprises following action: the calibration curve of storage is provided, and described calibration curve has been represented the feature of the described secondary measured value of described secondary influence.

12. method as claimed in claim 10, be used to realize to be used for biology sensor, based on the correction function of threshold value, wherein, definite response is in the described correction function of the described first coefficient A that is determined, and definite response comprises following action in the action of the described correction function of the described second coefficient I that is determined: determine the linear function at described correction function.

13. method as claimed in claim 10, be used to realize to be used for biology sensor, based on the correction function of threshold value, wherein, definite response is in the described correction function of the described first coefficient A that is determined, and definite response comprises following action in the action of the described correction function of the described second coefficient I that is determined: determine the nonlinear function at described correction function.

14. the method for claim 1, be used to realize to be used for biology sensor, based on the correction function of threshold value, wherein, obtain the action of the secondary measured value of secondary influence is comprised following action: obtain measured temperature.

15. the method for claim 1, be used to realize to be used for biology sensor, based on the correction function of threshold value, to be glucose and wherein said acquisition comprise following action to the action of the secondary measured value of secondary influence to wherein said analyte: obtain the hemoglobinometry value.

16. the method for claim 1, be used to realize to be used for biology sensor, based on the correction function of threshold value, wherein, to be glucose and wherein said acquisition comprise following action to the action of the secondary measured value of secondary influence to described analyte: the measured value that obtains to show hematocrit concentration.

17. the method for claim 1, be used to realize to be used for biology sensor, based on the correction function of threshold value, wherein, described analyte is glucose and wherein obtains the action of the secondary measured value of secondary influence is comprised following action: obtain to show the measured value of hematocrit concentration and obtain measured temperature.

18. a device is used to realize the correction function based on threshold value, described device comprises:

Be used to obtain the biology sensor of sample;

With the processor of described biology sensor coupling connection, described processor responds to the described biology sensor that is used to obtain described sample, is used to obtain to treat the primary measurement values of analyte value;

Described processor is used to obtain the secondary measured value to secondary influence;

Described processor is used for the described secondary measured value and the threshold value of described secondary influence are compared;

Described processor responds to the described value that is compared, and uses at least one coefficient value to determine correction function, and wherein said at least one coefficient value depends on the described primary measurement values of described analysans value; And

Described processor is used for the described correction function that is determined is applied to described primary measurement values, so that the analysans value through overcorrect to be provided.

19. device as claimed in claim 18, be used to realize correction function based on threshold value, described device comprises: the calibration curve of storage, determine described correction function by described processor with it, and described calibration curve has been represented the feature of the described secondary measured value of described secondary influence.

20. device as claimed in claim 18, be used to realize correction function based on threshold value, wherein, described processor responds to the result who the described secondary measured value of described secondary influence is confirmed as being less than or equal to described threshold value, be used for determining the first coefficient A, the described first coefficient A is used to control the amplitude of described correction function.

21. device as claimed in claim 20, be used to realize correction function based on threshold value, wherein, described processor responds to described secondary measured value to described secondary influence and is confirmed as result greater than described threshold value, be used for determining the second coefficient I, the described second coefficient I is used to control the amplitude of described correction function.

Images