HK1218777B - Methods of scaling data used to construct biosensor algorithms as well as devices, apparatuses and systems incorporating the same - Google Patents

Description

Method of scaling data for constructing biosensor algorithms and apparatus, device and system incorporating the same

Cross reference to related applications

This patent application claims priority to U.S. provisional patent application No.61/794,280 filed on 3, 15, 2013, which is incorporated herein by reference as if set forth in its entirety.

Technical Field

The present disclosure relates generally to mathematics and medicine, and more particularly, to methods of scaling bodily fluid analysis measurement data to correct and/or compensate for confounding variables such as hematocrit (Hct), temperature, raw material variations such as electrode conductivity, or combinations thereof, prior to providing an analyte concentration.

Background

Many analyte measurement systems, such as self-monitoring blood glucose (SMBG) systems, clinical blood glucose monitoring systems, and laboratory blood glucose monitoring systems, are based on amperometric, coulometric, potentiometric, voltage-metric, or other electrical measurements of electroactive species produced by reactions with analytes such as glucose or measurements of direct properties of analyte matrices. Combinations of these methods may also be used to calculate analyte concentrations.

In SMBG systems, electrochemical measurements are typically performed by inserting a biosensor into a handheld meter and introducing a droplet of a liquid sample, such as blood, onto the biosensor having a defined sample space, dried chemical reagents and an electrode system. When a sample is detected, the meter then performs an electrical measurement, and a mathematical algorithm converts the response data into a reliable glucose concentration.

For example, in single-potential, DC-based amperometric measurements, a potential is applied to a liquid sample containing an electroactive analyte, and the current is monitored as the analyte is reduced or oxidized. The resulting DC current exhibits a time decay as described by the Cottrell equation. As the slope of the attenuation decreases and approaches a constant rate of change with respect to time, the magnitude of the current can be used to quantify the analyte.

However, the magnitude, rate, and shape of the current decay may be affected by many variables including, but not limited to, reagent thickness, wetting of the reagent, rate of sample diffusion, Hct and temperature, and the presence of certain interferents. These interferents or confounding variables may cause an increase or decrease in the observed magnitude of the DC current proportional to the analyte, such as glucose, resulting in a deviation from the "true" glucose concentration.

The current methods and systems provide some advantages with respect to convenience; however, there remains a need for a measurement method that can correct or otherwise compensate for confounding variables.

Disclosure of Invention

In view of the above-identified shortcomings, the present disclosure describes methods of compensating for or correcting for effects that certain confounding variables may have when measuring an analyte concentration in a liquid sample, thereby providing a "true" analyte concentration. The method is based on an inventive concept comprising: prior to using the algorithm that provides the analyte concentration, information derived from an Alternating Current (AC) response is used in order to scale data from higher amplitude responses, such as DC measurements, in a manner that reduces the effects of confounding variables. The inventive concept thus provides certain advantages, effects, features and objects when compared to known methods of measuring analyte concentrations in liquid samples.

In one aspect, a scaling method is provided to compensate for or correct for variations in electrode conductivity. The method comprises the following steps: measuring at least two loop resistances of an electrode system on a biosensor, normalizing each of the at least two loop resistances by dividing each by a separate constant, and scaling the current response by incorporating the lower of the normalized loop resistances (i.e., the smallest) into an algorithm for determining analyte concentration or into a failsafe (failsafe). The method further comprises the following steps: a test sequence having an AC block and at least one DC block is applied to a bodily fluid sample and AC and DC current responses are measured.

One of the at least two loop resistances may be measured from a contact pad associated with the conductive trace of the working electrode. Another of the at least two loop resistances may be measured from a contact pad associated with the conductive trace of the counter electrode.

Each constant used to normalize the loop resistance may be a predetermined median resistance value obtained by measuring the corresponding loop resistance in one or more batches of biosensors.

As for the AC block, it may be a block of low amplitude signals applied simultaneously, sequentially or in parallel. In some examples, the AC block includes at least two different low amplitude signals. For example, an AC block may include two (2) segments at two (2) frequencies, such as, for example, about 10kHz or about 20kHz followed by about 1kHz or about 2 kHz. In other examples, the AC block includes a plurality of low amplitude signals. For example, an AC block may have five (5) segments at four (4) frequencies, such as, for example, about 10kHz, about 20kHz, about 10kHz, about 2kHz, and about 1 kHz. Alternatively, the AC block may have four (4) segments at four (4) frequencies, such as, for example, about 20kHz, about 10kHz, about 2kHz, and about 1 kHz. Alternatively, the AC block may have four (4) frequencies applied at about 10kHz, about 20kHz, about 10kHz, about 2kHz, and about 1kHz simultaneously. Still alternatively, the AC block may have a multi-frequency excitation waveform that simultaneously applies the desired low-amplitude AC signal.

In some examples, the AC block is applied for about 500msec to about 1.5 sec. In other examples, the AC block is applied for about 100msec to about 300 msec.

With respect to the DC block, it may include at least one (1) pulse to about ten (10) pulses at a potential that alternates between about 0mV to about +450 mV. In some examples, the DC block may be a single potential step from about 0mV to about +450mV, where the potential is maintained such that a decaying current response may be detected. That is, the DC block includes at least one excitation pulse and at least one recovery pulse, wherein the pulses alternate between about 0mV to about +450 mV.

Regardless of the number of pulses, each DC pulse may be applied for about 50msec to about 500 msec. For example, each DC pulse at +450mV may be applied for approximately 250msec, and each DC pulse at 0mV may be applied for approximately 500 msec.

In some examples, the AC block is applied before, after, or interspersed within the DC block.

The electrodes may include conductive layers of aluminum, carbon, copper, gold, indium tin oxide, palladium, platinum, titanium, or mixtures thereof.

These normalized loop resistances may thus be used as part of an algorithm that can correct for changes during calculation of analyte concentration, and/or may be used to trigger device failsafe that prevents display/reporting of analyte concentration in the event that changes in electrode conductivity exceed a predetermined threshold.

In another aspect, a scaling method is provided to compensate or correct for low or high Hct during bodily fluid analysis for an analyte of interest. The method may comprise the steps of: applying an AC block to a body fluid sample together with at least one DC block, measuring AC and DC current responses, calculating solution resistance (R) from AC block signals and current responses_solution) And the DC current response is compared with R_solutionThe multiplication results in a compensated voltage drop that minimizes the effect of Hct on the estimated analyte concentration.

With respect to the AC block, it may be a plurality of low amplitude signals applied simultaneously, either sequentially or in parallel. In some examples, the AC block includes at least two different low amplitude signals. For example, an AC block may include two (2) segments at two (2) frequencies, such as, for example, about 10kHz or about 20kHz followed by about 1kHz or about 2 kHz. Alternatively, the AC block may have five (5) segments at four (4) frequencies, such as, for example, about 10kHz, about 20kHz, about 10kHz, about 2kHz, and about 1 kHz. Alternatively, the AC block may have four (4) segments at four (4) frequencies, such as, for example, about 20kHz, about 10kHz, about 2kHz, and about 1 kHz. Alternatively, the AC block may have four (4) frequencies applied at about 10kHz, about 20kHz, about 10kHz, about 2kHz, and about 1kHz simultaneously. Still alternatively, the AC block may have a multi-frequency excitation waveform that simultaneously applies the desired low-amplitude AC signal.

In some examples, the AC block is applied for about 500msec to about 1.5 sec. In other examples, the AC block is applied for about 100msec to about 300 msec.

With respect to the DC block, it may include at least one (1) pulse to about ten (10) pulses at a potential that alternates between about 0mV to about +450 mV. In some examples, the DC block is a single potential step from about 0mV to about +450mV, where the potential is maintained such that a decaying current response can be detected. That is, the DC block includes at least one excitation pulse and at least one recovery pulse, wherein the pulses alternate between about 0mV to about +450 mV.

Regardless of the number of pulses, each DC pulse may be applied for about 50msec to about 500 msec. In particular, each DC pulse at approximately +450mV may be applied for approximately 250msec, and each DC pulse at approximately 0mV may be applied for approximately 500 msec.

In some examples, the AC block is applied before, after, or interspersed within the DC block.

The method may further comprise the step of constructing an algorithm incorporating the Hct compensated voltages to provide an estimated analyte concentration.

In another aspect, a scaling method is provided to compensate for Hct and/or temperature during a bodily fluid analysis for an analyte of interest. The method comprises the following steps: applying an AC block to the body fluid sample together with the at least one DC block, measuring the AC and DC current responses, calculating the admittance (Y) from at least one of the AC signal and the response, and dividing the DC current response by the admittance (Y) to obtain a compensated current that minimizes the effect of Hct and/or temperature on the DC current and thus on the analyte concentration.

With respect to the AC block, it may be a plurality of low amplitude signals applied simultaneously, either sequentially or in parallel. In some examples, the AC block includes at least two different low amplitude signals. For example, an AC block may include two (2) segments at two (2) frequencies, such as, for example, about 10kHz or about 20kHz followed by about 1kHz or about 2 kHz. Alternatively, the AC block may have five (5) segments at four (4) frequencies, such as, for example, about 10kHz, about 20kHz, about 10kHz, about 2kHz, and about 1 kHz. Alternatively, the AC block may have four (4) segments at four (4) frequencies, such as, for example, about 20kHz, about 10kHz, about 2kHz, and about 1 kHz. Alternatively, the AC block may have four (4) frequencies applied at about 10kHz, about 20kHz, about 10kHz, about 2kHz, and about 1kHz simultaneously. Still alternatively, the AC block may have a multi-frequency excitation waveform that simultaneously applies the desired low-amplitude AC signal.

In some examples, the AC block is applied for about 500msec to about 1.5 sec. In other examples, the AC block is applied for about 100msec to about 300 msec.

With respect to the DC block, it may include at least one (1) pulse to about ten (10) pulses at a potential that alternates between about 0mV to about +450 mV. In some examples, the DC block may be a single potential step from about 0mV to about +450mV, where the potential is maintained such that a decaying current response may be detected. That is, the DC block includes at least one excitation pulse and at least one recovery pulse, wherein the pulses alternate between about 0mV to about +450 mV.

Regardless of the number of pulses, each DC pulse may be applied for about 50msec to about 500 msec. For example, each DC pulse at +450mV may be applied for approximately 250msec, and each DC pulse at 0mV may be applied for approximately 500 msec.

In some examples, the AC block is applied before, after, or interspersed within the DC block.

In some examples, the admittance (Y) is calculated at 20kHz (Y)₂₀）。

The method may further include the step of constructing an algorithm that incorporates the Hct and/or temperature compensated current to provide an estimated analyte concentration.

In another aspect, an associated scaling method is provided to compensate for Hct and/or temperature during bodily fluid analysis for an analyte of interest. The method comprises the following steps: applying an AC block together with at least one DC block to the body fluid sample, measuring AC and DC current responses, calculating an optimal power of the admittance (Y) from at least one of the AC signal and the response, and dividing the DC current response by the exponentiated admittance (Y) to obtain a compensated current that minimizes the effect of Hct and/or temperature on the DC current and thus on the analyte concentration.

With respect to the AC block, it may be a plurality of low amplitude signals applied simultaneously, either sequentially or in parallel. In some examples, the AC block includes at least two different low amplitude signals. For example, an AC block may include two (2) segments at two (2) frequencies, such as, for example, about 10kHz or about 20kHz followed by about 1kHz or about 2 kHz. Alternatively, the AC block may have five (5) segments at four (4) frequencies, such as, for example, about 10kHz, about 20kHz, about 10kHz, about 2kHz, and about 1 kHz. Alternatively, the AC block may have four (4) segments at four (4) frequencies, such as, for example, about 20kHz, about 10kHz, about 2kHz, and about 1 kHz. Alternatively, the AC block may have four (4) frequencies applied at about 10kHz, about 20kHz, about 10kHz, about 2kHz, and about 1kHz simultaneously. Still alternatively, the AC block may have a multi-frequency excitation waveform that simultaneously applies the desired low-amplitude AC signal.

In some examples, the AC block is applied for about 500msec to about 1.5 sec. In other examples, the AC block is applied for about 100msec to about 300 msec.

With respect to the DC block, it may include at least one (1) pulse to about ten (10) pulses at a potential that alternates between about 0mV to about +450 mV. In some examples, the DC block may be a single potential step from about 0mV to about +450mV, where the potential is maintained such that a decaying current response may be detected. That is, the DC block includes at least one excitation pulse and at least one recovery pulse, wherein the pulses alternate between about 0mV to about +450 mV.

Regardless of the number of pulses, each DC pulse may be applied for about 50msec to about 500 msec. For example, each DC pulse at +450mV may be applied for approximately 250msec, and each DC pulse at 0mV may be applied for approximately 500 msec.

In some examples, the AC block is applied before, after, or interspersed within the DC block.

The method may further include the step of constructing an algorithm incorporating Hct and/or temperature compensated voltages to provide an estimated analyte concentration.

In view of the foregoing, devices, apparatuses, and systems are provided for use in connection with bodily fluid analysis that incorporate one or more of the scaling methods disclosed herein. These devices, apparatuses, and systems may be used to determine the concentration of analytes including, but not limited to, amino acids, antibodies, bacteria, carbohydrates, drugs, lipids, markers, nucleic acids, peptides, proteins, toxins, viruses, and other analytes, and combinations thereof. In certain examples, the analyte is glucose.

These and other advantages, effects, features and objects of the inventive concept will become better understood from the following description. In this description, reference is made to the accompanying drawings which form a part hereof, and in which there is shown by way of illustration, and not limitation, embodiments of the inventive concept.

Drawings

Advantages, effects, features and objects other than those set forth above will become more readily apparent when consideration is given to the following detailed description. Such detailed description makes reference to the following drawings, in which:

fig. 1 illustrates an exemplary analyte measurement system including a meter and a biosensor.

Fig. 2 shows a top view of an exemplary biosensor electrode system for electrochemically determining an analyte concentration in a liquid sample.

Fig. 3A-C illustrate exemplary test signals that may be employed by an analyte testing apparatus, device, or system.

Fig. 4 illustrates an exemplary scaling method.

Fig. 5A-C are graphs illustrating the results of an AC frequency analysis performed in conjunction with the exemplary scaling process of fig. 4.

6A-C are diagrams illustrating R performed in connection with the exemplary scaling process of FIG. 4_solutionPlots of the effect of scaling on AC and DC data.

FIG. 7 is a graph showing DC current measurement (DC 1124) and admittance (Y)₂₀) Graph of the relationship between.

FIG. 8 is a graph showing the phase angle (θ) and admittance (Y)₂₀) Graph of the relationship between.

Fig. 9 is a graph illustrating Pearson's (Pearson) correlation between scaled DC and power exponent.

Fig. 10 is a graph illustrating pearson correlation between scaled DC and power exponent.

FIG. 11 shows R_conductorTwo graphs of the benefit of the change in electrode conductivity are scaled.

While the inventive concept is susceptible to various modifications and alternative forms, exemplary embodiments thereof have been shown by way of example in the drawings and are herein described in detail. It should be understood, however, that the description herein of exemplary embodiments is not intended to limit the inventive concepts to the particular forms disclosed, but on the contrary, the intention is to cover all advantages, effects, features and objects falling within the spirit and scope of the embodiments as described herein and defined by the following claims. Therefore, reference should be made to the embodiments described herein and the following claims for purposes of explaining the scope of the inventive concept. As such, it should be noted that the embodiments described herein may have advantages, effects, features and objects that are useful in solving other problems.

Detailed Description

Methods, apparatus, devices, and systems will now be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all embodiments of the inventive concepts are shown. Indeed, the inventive concept may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements.

As such, many modifications and other embodiments of the methods, apparatus, devices, and systems described herein will come to mind to one skilled in the art to which this disclosure pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the inventive concepts are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present methods, devices, apparatuses and systems, the preferred methods and materials are described herein.

Moreover, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there be one and only one of the elements. The indefinite article "a" or "an" thus usually means "at least one".

SUMMARY

Disclosed herein are scaling methods that use response information derived from AC potentials to scale DC response data in a manner that reduces the effect of confounding variables on analyte concentration. These scaling methods can therefore be used to reduce the effect of confounding variables such as Hct and/or temperature on the observed DC current response-prior to creating the algorithm. Likewise, the scaling method may also be used to reduce the effect of variations in electrode conductivity, particularly variations caused by variations in raw materials and non-uniform resistance among the electrodes in the electrode system.

Advantageously, the scaling methods disclosed herein may be used in algorithms that deliver more accurate and reliable analyte concentration measurements and fail-safe during use of various electrochemical measurement methods, including amperometry. If fail safe is triggered, the analyte concentration measurement device, apparatus or system may be configured to deliver an error code or error message rather than an inaccurate analyte concentration. For example, fail-safe may include direct messaging, such as: "a conductive layer error in the biosensor is detected and therefore an analyte concentration cannot be reported". This may result in the healthcare professional or user continuing to determine the cause and find a suitable device or biosensor that may not have the problem.

The scaling method may also be applied prior to other electrochemical methods such as voltage or coulometry, potentiometry, or analysis of voltage measurement data, where the current (or in this case, scaled/compensated current) is summed to produce a charge (Q) that is collected during the period of the applied potential or potential pulse sequence. Additional details regarding exemplary electrochemical measurement methods are disclosed, for example, in U.S. Pat. Nos.; 4,891,319; 4,999,582;;; 5,120,420; 5,122,244;;;;; 5,437,999,271; U.S. Pat. No.; 5,762,770;; 5,997,817;;;;;; 6,270,637; 6,368; U.S. Pat. No.; 7,073,246; U.S. Pat. No.; U.S. Pat. No.; U.S. Pat. No.; is hereby incorporated herein by reference in its entirety, or in its entirety, and in its entirety, respectively, and in its entirety, and in their entirety, U.S. Pat. Patents).

Advantageously, the methods described herein may be incorporated into SMBG apparatus, devices, and systems to reduce the effects of Hct and/or temperature on reported analyte concentrations (such as glucose concentrations). Likewise, other methods described herein may be incorporated into SMBG apparatus, devices, and systems to reduce the effect of changes in electrical conductors or other raw materials on reported analyte concentrations.

Moreover, these scaling methods may be implemented using advanced microprocessor-based algorithms and processes, which result in significantly improved system performance. These methods also provide flexibility and many ways to create algorithms that can achieve improved performance, such as 10/10 performance. As used herein, "10/10 performance" means: for bG concentrations >100mg/dL, the measured bG values are within about 10% of the actual bG values, and for bG concentrations <100mg/dL, the measured bG values are within 10mg/dL of the actual bG values.

Details regarding additional electrochemical measurement methods that may be useful in performing the methods disclosed herein may be found in the following co-pending patent applications, entitled: "METHODS OF Electrochenogenetic training AN ANALYTE WITH A TEST SEQUENCE A pulse DC BLOCK AS WELL ASDEVICES, APPARATUSES AND SYSTEMS INCORPORATING THE SAME" Applicant's docket Nos. 31519 and 31521; "METHODS OF FAILSAFING ELECTROCHEMICAL MEASUREMENTS OF AN ANALYTE ASWELL AS DEVICES, APPARATUSES AND SYSTEMS INCORPORATING THE SAME" case No. 31520; "METHODS OF USING INFORMATION FROM FROM RECOVERY PULSES IN ELECTROCHEMICAL ANALYTEMEASUREMENTS AS WELL AS DEVICES, APPARATUSES AND SYSTEMS INCORPORATING THESAME" case No. 31522; record No. 31523, "describe-BASED METHODS OF Electrochenoanalysis MEASURING ANANALYTE AS WELL AS DEVICES, APPARATUSES AND SYSTEMS Incoporting THE SAME"; and "METHODS OF DETECTING HIGH ANTIOXIDANT leaves OF environmental protection systems AND FAILSAFING AN ANALYTE conditional recovery from AS WELL AS DEVICES, APPARATUSES AND SYSTEMS inhibiting SAME" case number 31524.

Analyte measurement device, apparatus and system

Before describing the measurement method of the present invention and in conjunction therewith, FIG. 1 shows an exemplary analyte measurement system including a device, such as a test meter 11, operatively coupled to an electrochemical biosensor 20 (also known as a test element). Meter 11 and biosensor 20 are operable to determine the concentration of one or more analytes in a liquid sample provided to biosensor 20. In some examples, the sample may be a bodily fluid sample, such as, for example, whole blood, plasma, serum, urine, or saliva. In other examples, the liquid sample may be another type of sample to be tested for the presence or concentration of one or more electrochemically reactive analytes, such as an aqueous environment sample.

In fig. 1, the biosensor 20 is a single use test strip that is removably inserted into the connection terminal 14 of the meter 11. In some examples, biosensor 20 is configured as a blood glucose test element and includes features and functionality for electrochemically measuring glucose. In other examples, the biosensor 20 is configured to electrochemically measure one or more other analytes, such as, for example, amino acids, antibodies, bacteria, carbohydrates, drugs, lipids, markers, nucleic acids, peptides, proteins, toxins, viruses, and other analytes.

The meter 11 includes: an electronic display 16 for displaying various types of information to a user, including analyte concentration(s) or other test results; and a user interface 50 for receiving user input. The meter 11 also includes a microcontroller and associated test signal generation and measurement circuitry (not shown) operable to generate a test signal, apply the signal to the biosensor 20, and measure one or more responses of the biosensor 20 to the test signal. In some examples, the Meter 11 may be configured as a blood glucose measuring Meter and include the features and functions of ACCU-CHEK AVIVA TYVET instruments as described in the brochure "Accu-Chek Aviva BlodGlucose Meter Owner's Booklet" (2007), which is disclosed in part in U.S. Pat. No.6,645,368. In other examples, the meter 11 may be configured to electrochemically measure one or more other analytes such as, for example, amino acids, antibodies, bacteria, carbohydrates, drugs, lipids, markers, nucleic acids, proteins, peptides, toxins, viruses, and other analytes. Additional details regarding exemplary meters configured for use with electrochemical measurement methods are disclosed in, for example, U.S. Pat. Nos. 4,720,372; 4,963,814; 4,999,582; 4,999,632; 5,243,516; 5,282,950; 5,366,609; 5,371,687; 5,379,214; 5,405,511; 5,438,271; 5,594,906; 6,134,504; 6,144,922; 6,413,213; 6,425,863; 6,635,167; 6,645,368; 6,787,109; 6,927,749; 6,945,955; 7,208,119; 7,291,107; 7,347,973; 7,569,126; 7,601,299; 7,638,095 and 8,431,408.

Those skilled in the art will appreciate that the scaling methods described herein may be used in other measurement devices, apparatuses, systems, and environments, such as, for example, hospital testing systems, laboratory testing systems, and others.

It should be understood that the biosensor and meter may include additional and/or alternative attributes and features in addition to or instead of those shown in fig. 1. For example, the biosensor may be in the form of a single-use disposable electrochemical test strip having a substantially rectangular shape. It should be appreciated that the biosensor may comprise different forms, such as, for example, different configurations, sizes, or shapes of test strips, non-strip-shaped test elements, disposable test elements, reusable test elements, microarrays, lab-on-a-chip devices, biochips, bio-discs, bio-cds, or other test elements.

Fig. 2 shows a more detailed view of an exemplary biosensor 100 comprising a substrate 110 and an arrangement of conductive material provided on the substrate 110. The substrate 110 may be polyethylene terephthalate ("PET"). The substrate 110 may also comprise other materials including, for example, polyester or other polymeric or thermoplastic materials, among others. The conductive material on the substrate 110 includes a material, such as gold or a gold alloy, that may be provided on the substrate to define the electrodes and/or code pattern. Additional materials that may be used include, but are not limited to, platinum, palladium, iridium, or alloys thereof.

Also shown in fig. 2 is an exemplary pattern of conductive material that may be useful for a biosensor provided for an electrochemical liquid sample analysis system. Other biosensors may include a variety of other conductive patterns useful in performing electrochemical analyte measurements. A conductive material is typically disposed on the substrate 110 to provide a number of conductive paths. The particular arrangement of conductive material, such as the arrangement illustrated in fig. 2, may be provided using a number of techniques, including chemical vapor deposition, laser ablation, lamination, screen printing, photolithography, and combinations of these and other techniques. One illustrated conductive path includes working electrode 121, working electrode contact pads 123a and 123b, and conductive trace portions 125a and 125b extending between working electrode 121 and working electrode contact pads 123a and 123b and electrically coupling working electrode 121 with working electrode contact pads 123a and 123 b.

An alternative conductive path shown in fig. 2 includes the counter electrode 120 (illustrated as including double teeth), the counter electrode contact pads 124a and 124b, and conductive trace portions 126a and 126b that extend between the counter electrode 120 and the counter electrode contact pads 124a and 124b and electrically couple the counter electrode 120 and the counter electrode contact pads 124a and 124 b.

Another conductive path shown in fig. 2 includes a sample sufficiency electrode 131, a sample sufficiency contact pad 135, and a conductive trace portion 133 that extends between the sample sufficiency electrode 131 and the sample sufficiency contact pad 135 and electrically couples the sample sufficiency electrode 131 and the sample sufficiency contact pad 135. Another illustrated conductive path includes a sample sufficiency electrode 132, a sample sufficiency contact pad 136, and a conductive trace portion 134 extending between the sample sufficiency electrode 132 and the sample sufficiency contact pad 136 and electrically coupling the sample sufficiency electrode 132 and the sample sufficiency contact pad 136. The sample sufficiency electrodes 131 and 132 may be used to implement a number of techniques for determining the sufficiency of a test sample provided to the test element 100.

During testing operations involving biosensor 100, working electrode contact pads 123a and 123b may be coupled to a working electrode terminal of the meter, counter electrode contact pads 124a and 124b may be coupled to a counter electrode terminal of the meter, and sample sufficiency contact pads 135 and 136 may be coupled to respective sample detection terminals of the meter. A liquid sample to be analyzed may be provided to the biosensor 100, for example by introducing the liquid sample into a sample chamber. The meter and biosensor 100 may be used to check the alignment of a test element with respect to the meter, perform a failsafe or error checking function (e.g., verifying the integrity of the conductive path by testing for expected electrical characteristics between working electrode contact pads 123a and 123b or counter electrode contact pads 124a and 124 b), perform fill detection and sample sufficiency detection functions with pads 135 and 136, and perform an electrochemical analysis function, such as blood glucose concentration measurement or detection or measurement of other analytes.

Additional details regarding exemplary biosensors configured for use with electrochemical measurement methods are disclosed in, for example, U.S. Pat. Nos. 5,694,932, 5,762,770, 5,948,695, 5,975,153, 5,997,817, 6,001,239, 6,025,203, 6,162,639, 6,245,215, 6,271,045, 6,319,719, 6,406,672, 6,413,395, 6,428,664, 6,447,657, 6,451,264, 6,455,324, 6,488,828, 6,506,575, 6,540,890, 6,562,210, 6,582,573, 6,592,815, 6,627,057, 6,638,772, 6,755,949, 6,767,440, 6,780,296, 6,780,651, 6,814,843, 6,814,844, 6,858,433, 6,866,758, 7,008,799, 7,063,774, 7,238,534, 7,473,398, 7,476,827, 7,479,211, 7,510,643, 7,727,467, 7,780,827, 7,820,451, 7,867,369, 7,892,849, 8,180,423, 8,298,401, 8,329,026, and 42560, RE42924 and 42953.

Scaling method

As indicated above, the scaling method described herein is based on the following inventive concept, which includes: prior to constructing the descriptors and algorithms that provide the analyte concentration, information derived from the AC signal and current response is used to scale the amperometric data in a manner that attenuates, minimizes, or reduces the effects of confounding variables. In particular, the scaling method uses information derived from the AC current response to compensate or correct for the effects of confounding variables such as Hct and/or temperature and changes in the electrical conductor raw material on the reported analyte concentration.

Some steps common among methods are applying an AC block of low amplitude signals along with a DC block to a liquid sample such as a bodily fluid and measuring the current response thereto. Fig. 3A-C illustrate exemplary test sequences that may be used in connection with SMBG and other test systems. As shown in fig. 3A-B, the test sequence may include one or more blocks of AC and/or DC potentials. For example, an AC block of a test sequence may include a low amplitude signal followed by a controlled DC block, such as: (1) an AC block of a plurality of segments at different frequencies; and (2) a DC block of similar short duration (e.g., about 50-500 msec) about +450mV pulses separated by short duration (e.g., about 50-500 msec) recovery pulses during which a closed circuit about 0mV recovery potential is applied.

With respect to the AC block, it may include a plurality of AC segments, such as, for example, from about 2 segments to about 10 segments, from about 3 segments to about 9 segments, from about 4 segments to about 8 segments, from about 5 segments to about 7 segments, or about 6 segments. In other examples, the AC block may include about 2 segments, about 3 segments, about 4 segments, about 5 segments, about 6 segments, about 7 segments, about 8 segments, about 9 segments, or about 10 segments. In still other examples, the AC block may have more than 10 segments, that is, about 15 segments, about 20 segments, or about 25 segments. In yet other examples, the AC block may include 1 segment with multiple low frequency AC signals applied simultaneously.

Those skilled in the art understand that the number of AC segments will be limited by the complexity of the response, the associated frequency range, and the time available to perform the measurements. Higher frequencies generally require high bandwidth electronics and faster sampling, while lower frequencies take longer and are typically more noisy. The maximum number of segments will therefore be a compromise between these parameters, the minimum count and frequency span required to select the distinguishing samples, and the environment and/or confounding factors of interest.

As used herein, "about" means within a statistically significant range of one or more values, such as a specified concentration, length, molecular weight, pH, potential, time frame, temperature, voltage, or volume. Such values or ranges may be within an order of magnitude, typically within 20%, more typically within 10%, and even more typically within 5% of a given value or range. The permissible variations encompassed by "about" will depend on the particular system under study and can be readily appreciated by one skilled in the art.

The frequency of each signal in each segment of the AC block may be from about 1kHz to about 20kHz, from about 2kHz to about 19 kHz, from about 3kHz to about 18 kHz, from about 4 kHz to about 17 kHz, from about 5 kHz to about 16 kHz, from about 6kHz to about 15 kHz, from about 7 kHz to about 14 kHz, from about 8 kHz to about 13kHz, from about 9 kHz to about 12 kHz, or from about 10kHz to about 11 kHz. In other examples, the frequency of each segment in the AC block may be about 1kHz, about 2kHz, about 3kHz, about 4 kHz, about 5 kHz, about 6kHz, about 7 kHz, about 8 kHz, about 9 kHz, about 10kHz, about 11 kHz, about 12 kHz, about 13kHz, about 14 kHz, about 15 kHz, about 16 kHz, about 17 kHz, about 18 kHz, about 19 kHz, or about 20 kHz. In still other examples, the frequency of each signal in each segment of the AC block may be greater than 20kHz, that is, about 30 kHz, about 40 kHz, or about 50 kHz. In some instances, one or more segments may have the same frequency, while in other instances, each segment has a different frequency than the other segments. However, four frequencies are generally suitable. The exact frequency employed can be easily generated by simple integer division of the maximum frequency of the measurement system clock.

However, for inexpensive, battery-powered hand-held instruments, the maximum frequency limit for signals in the segments of the AC block may be up to about 100 kHz. In addition to this, the increasing demands on analog bandwidth, sampling rate, storage and processing speed add up rapidly, while the imaginary part of a typical biosensor response becomes increasingly smaller with frequency. Lower frequencies have longer periods and take longer to sample with comparable accuracy.

An AC block typically includes at least two different low amplitude signals. For example, an AC block may include two (2) segments at two (2) frequencies, such as, for example, about 10kHz or about 20kHz followed by about 1kHz or about 2 kHz. In other examples, the AC block includes a plurality of low amplitude signals. For example, an AC block may have five (5) segments at four (4) frequencies, such as, for example, about 10kHz, about 20kHz, about 10kHz, about 2kHz, and about 1 kHz. Alternatively, the AC block may have four (4) segments at four (4) frequencies, such as, for example, about 20kHz, about 10kHz, about 2kHz, and about 1 kHz. Alternatively, the AC block may have four (4) frequencies applied at about 10kHz, about 20kHz, about 10kHz, about 2kHz, and about 1kHz simultaneously. Still alternatively, the AC block may have a multi-frequency excitation waveform that simultaneously applies the desired low-amplitude AC signal. The AC frequencies may be applied sequentially, or combined and applied simultaneously and analyzed via fourier transform.

Blocks of low amplitude AC signals may be applied for about 500msec to about 1.5sec, about 600msec to about 1.25sec, about 700msec to about 1000msec, or about 800msec to about 900 msec. Alternatively, blocks of low amplitude AC signals may be applied for about 500msec, about 600msec, about 700msec, about 800msec, about 900msec, about 1000msec, about 1.25sec, or about 1.5 sec. In particular, blocks of low amplitude AC signals may be applied for about 100msec to about 300 msec.

However, one skilled in the art understands that the number, frequency, duration, and order of the AC segments may vary.

The AC current response information may be obtained at any time during the test sequence. The impedance results at lower frequencies may be affected by the analyte concentration if obtained after the electrochemical cell is DC polarized. In some instances, a series of AC current response measurements may be obtained early in the test sequence. Measurements taken shortly after the liquid sample is applied to the biosensor will be affected by diffusion, temperature and reagent solubility. In other examples, the AC response current measurement may be obtained at a sufficient time after the appropriate sample has been applied to allow the response to stabilize and avoid a transient response in the first second. Likewise, the response current measurements may be made at one or more frequencies. Due to its capacitive nature, multiple AC measurements separated by octaves or decimals may provide different sensitivities or easier manipulation.

Additional details regarding exemplary AC blocks in electrochemical measurement methods are disclosed in, for example, U.S. Pat. nos. 7,338,639, 7,390,667, 7,407,811, 7,417,811, 7,452,457, 7,488,601, 7,494,816, 7,597,793, 7,638,033, 7,751,864, 7,977,112, 7,981,363, 8,148,164, 8,298,828, 8,377,707, and 8,420,404.

With respect to the DC block, it may include a plurality of pulses, such as, for example, from about 2 pulses to about 10 pulses, from about 3 pulses to about 9 pulses, from about 4 pulses to about 8 pulses, from about 5 pulses to about 7 pulses, or about 6 pulses. In other examples, the DC block may include about 2 pulses, about 3 pulses, about 4 pulses, about 5 pulses, about 6 pulses, about 7 pulses, about 8 pulses, about 9 pulses, or about 10 pulses. In still other examples, the DC block may have more than 10 pulses, that is, about 15 pulses, about 20 pulses, or about 25 pulses. As used herein, "pulse" means at least one excitation and one recovery period.

The DC block typically includes a constant applied potential difference alternating between about a 0mV and about a +450mV potential difference, or other slowly time-varying potential difference that can be analyzed by conventional DC electrochemical methods. However, it will be appreciated by those skilled in the art that the range of potential differences applied may and will vary depending on the analyte and the chemistry of the reagents used. As such, the excitation pulse potential may be greater than, less than, or equal to about +450 mV. Examples of excitation potentials include, but are not limited to, 50mV, 75mV, 100 mV, 125 mV, 150 mV, 175 mV, 200 mV, 225 mV, 250 mV, 275 mV, 300 mV,325 mV, 350 mV, 375 mV, 400 mV, 425 mV, 450mV, 475 mV, 500 mV, 525 mV, 550mV, 575 mV, 600 mV, 625 mV, 650 mV, 675 mV, 700 mV, 725 mV, 750 mV, 775 mV,800 mV, 825 mV, 850 mV, 875 mV, 900 mV, 925 mV, 950 mV, 975 mV, or 1000 mV.

Regardless of the number, each DC pulse may be applied for about 50msec to about 500msec, about 60msec to about 450 msec, about 70msec to about 400 msec, about 80 msec to about 350 msec, about 90msec to about 300msec, about 100msec to about 250msec, about 150 msec to about 200 msec, or about 175 msec. Alternatively, each pulse may be applied for about 50msec, about 60msec, about 70msec, about 80 msec, about 90msec, about 100msec, about 125 msec, about 150 msec, about 175msec, about 200 msec, about 225 msec, about 250msec, about 275 msec, about 300msec, about 325msec, about 350 msec, about 375 msec, about 400 msec, about 425 msec, about 450 msec, about 475msec, or about 500 msec. In particular, each DC pulse at +450mV may be applied for approximately 250msec, and each DC pulse at 0mV may be applied for approximately 500 msec. Still alternatively, each pulse may be applied for less than about 50msec or more than about 500 msec.

In general, the ramp rate of each DC pulse is selected to provide a reduction in peak current of about 50% or greater relative to the peak current provided by a near-ideal potential transition. In some examples, each pulse may have the same ramp rate. In other examples, some pulses may have the same ramp rate and other pulses may have different ramp rates. In still other examples, each pulse has its own ramp rate. For example, the effective ramp rate may be from about 5mV/msec to about 75 mV/msec or from about 10 mV/msec to about 50 mV/msec, 15 mV/msec to about 25 mV/msec, or about 20 mV/msec. Alternatively, the ramp rate may be about 5mV/msec, about 10 mV/msec, about 15 mV/msec, about 20 mV/msec, about 25 mV/msec, about 30mV/msec, about 35 mV/msec, about 40 mV/msec, about 45 mV/msec, about 50 mV/msec, about 55mV/msec, about 60 mV/msec, about 65 mV/msec, about 70 mV/msec, or about 75 mV/msec. In particular, the ramp rate may be from about 40 mV/msec to about 50 mV/msec.

Like the AC block, those skilled in the art will appreciate that the number, potential, duration and sequence of the DC pulses may vary.

AC and/or DC current response information is collected from the test sequence and includes current responses to the AC and DC blocks. In some instances, the current response information may be collected at an a/D sampling rate for DC and AC measurements to simplify system design, which includes a single shared signal path for AC and DC measurements. Common digital audio sample rates range from, but are not limited to, about 44.1kHz to about 192 kHz. a/D converters in this range are readily available from a variety of commercial semiconductor suppliers.

A more detailed test sequence is shown in fig. 3C, where one trace illustrates the applied DC potential and the other trace illustrates the AC and DC current responses accordingly. In this example, the applied DC potential may be fixed at about 0mV between pulses to provide a recovery pulse, thereby making it a generally continuous excitation waveform. This is in contrast to test sequences from known techniques which provide for the use of open circuits between positive DC pulses, thereby eliminating the possibility of collecting and analyzing the current between positive pulses.

As used herein, a "recovery pulse" means a zero potential pulse (e.g., about-10 mV to about +10 mV) applied for a suitably long recovery period, wherein the electrochemical reaction with the analyte of interest (e.g., glucose) is "cut off," allowing the system to return to a fixed starting point prior to subsequent interrogation with another positive DC pulse.

In a first exemplary scaling method (i.e., "R_solution"method"), a high frequency, low amplitude AC current response can be used to determine R by a classical Randles circuit model_solutionWhich can then be used to scale the DC current response. R_solutionScaling reduces the effect of high and low Hct levels. The method also comprisesIt is possible to use the transformed data to construct an algorithm with a linear form, leading to the possibility of simplifying the complexity of the algorithm.

Fig. 4 illustrates an example of a first scaling method based on analysis of AC response information using nyquist plots. The AC measurement described above in connection with FIG. 3C produces a complex impedance (Z) value that is nearly linear; however, there is a significant x-intercept. Assuming a classical Landes circuit model, the scaling method uses the x-intercept (extrapolated impedance) from a linear fit of four complex AC values as R_solutionWhich is strongly influenced by Hct and the salt content of the sample.

R calculated for each sample_solutionAnd then can be used to create compensated AC and DC values. For example, the DC current response value (in nA) can be compared with R_solutionThe direct multiplication yields a compensated voltage drop (in mV). This greatly minimizes the effect of Hct on the DC signal, leaving behind glucose as well as temperature effects.

The slope or angle (with respect to the origin) of the fitted impedance values for the AC block also describes the sample. Such AC information may be obtained by subtracting R from the actual real impedance_solutionAnd then calculate a new impedance magnitude for each frequency. The impedance magnitude may be converted to an admittance (Y) magnitude, and then real and imaginary admittance values and corresponding new angles may be calculated.

The AC information also characterizes the sample and may be correlated with the signal via R_solutionThe scaled/compensated DC values are combined to produce various algorithms. Interestingly, these scaled/compensated admittance values are independent of glucose and Hct effects and predominantly describe temperature.

In a second exemplary approach (i.e., a "factor" scaling approach), the AC current response may be used as a scaling factor for the DC current response to cancel out or substantially remove the effects of Hct and/or temperature on the DC signal, which is a major contributor to the predicted glucose value.

In a third exemplary method related to the factor scaling method (i.e., the "power" scaling method), a power may be applied to the AC current response to fine tune the scaling.

In the fourth exemplary method (i.e., "R_conductor"scaling method"), at least two loop resistances from the electrode system of the biosensor can be measured and then normalized by dividing each loop resistance by its own constant, respectively. The minimum value of the normalized loop resistance may then be incorporated into an analyte concentration algorithm or a failsafe calculation. Each constant may be obtained by taking the median of the corresponding loop resistance measured from the test batch or lots.

R_conductorScaling methods account for non-uniform resistance in the electrode system caused by, for example, raw material and manufacturing variations, scratches or cracks that may occur in post-manufacturing, and even contact resistance changes.

Examples of the invention

The inventive concept will be more fully understood when the following non-limiting examples are considered in view of illustration and not in limitation.

_solutionExample 1: and R scaling method.

This example shows the results of a first exemplary scaling method as shown in fig. 5A-C, which depict nyquist plots for large datasets of glycolide venous blood samples produced with an experimental design in which glucose, Hct, and temperature systematically varied in concert. The data set also contained dosed (spiked) plasma samples at three different salt levels. These results are from a large data set of glycolide venous blood samples with synergistic variation in glucose, Hct and temperature levels combined with a nominal feed plasma sample containing different salt levels.

Fig. 5A shows the complex AC response in the spectral levels and represents low to high Hct levels. One set of responses corresponds to plasma samples with different salt concentrations. Using the description above and in the figures4, R was obtained for each sample_solutionAnd then subtracted from each observed value of real impedance.

Warp R_solutionThe results of the compensation are shown in the graphs of fig. 5B-C. The two plots have the same value; however, the graph of fig. 5B is in the spectral level of Hct, and the graph of fig. 5C is in the spectral level of temperature. Fig. 5B shows evidence of residual Hct ordering, but all samples appear much more similar than in the above plot. In contrast, the graph of fig. 5C shows that temperature is the more dominant factor. Interestingly, no glucose information is encoded by the graphs of FIGS. 5A-C.

The results of the first exemplary scaling method are also shown in fig. 6A-F. The graphs of fig. 6A-B show that the measured admittance (Y) value at each frequency depends on both Hct and temperature, respectively. As indicated in fig. 6B, the cluster of data points with elevated admittance values corresponds to a plasma sample with elevated salt levels. By R_solutionThe effect of the compensation performed can be clearly seen in the lower and middle graphs, where the new admittance values are shown as a function of Hct and temperature, respectively.

The graph of fig. 6D shows the trend of no new admittance values at any of the four measured frequencies. The graph of fig. 6E shows a direct relationship with temperature and also shows that the accuracy of the new admittance value with respect to frequency is greatly improved. Also, the new admittance values for saline samples are more similar to other surrounding samples.

R for evaluation of DC measurement data_solutionThe effect of scaling, the data sets are sorted in order of decreasing glucose level, then by decreasing Hct level, and then by decreasing temperature. The graph of fig. 6C shows a single measured DC current value (from the last pulse in the applied sequence of electrical potentials) plotted for each sample in the sorted data set. The last three levels in the graph correspond to the spiked plasma samples with different salt concentrations.

From for BA ranked plot of DC current of lactide venous blood samples, possibly detecting six (6) glucose levels and five (5) Hct levels present in the data. Within each glucose level, it is noted that the highest (first) Hct level contains a lower DC current value, and the lowest (last) Hct level contains a higher DC value. In contrast, R of DC current value_solutionThe effect of scaling/compensation can be easily seen in the graph of fig. 6F. In particular, the Hct levels ("spiking") within each glucose level have much more similar amplitudes across all Hct levels.

Example 2: a factor scaling method.

A second exemplary scaling method is based on direct scaling of DC current measurements using admittance at 20 kHz. FIG. 7 shows a given DC current value with the measured admittance (Y) at 20kHz₂₀) The relationship between them. As described above, the measured Y₂₀Depending on both Hct level and temperature. A given DC amplitude may correspond to more than one glucose level due to Hct and temperature effects. The second exemplary scaling method is therefore based on calculating the selected DC current value and the corresponding Y for the same sample₂₀A new angle theta is formed therebetween. The value of θ is calculated according to the following equation:

θ = arctan (DC/Y20)。

the second exemplary scaling method produces the following situation: wherein θ is "orthogonal" to Y₂₀As seen in fig. 8, in an attempt to minimize the effect of Hct and temperature in the new variables. The effect is minimized because of the difference between θ and Y₂₀And the glucose level generated surface is smoother in fig. 7 than in fig. 8.

Example 3: "power" scaling methods.

The third scaling method is based on Y by being raised to an optimized power₂₀And scaling of DC current values, where power exponentials typically range from 0 to 10. The scaling method may be performed according to the following equation:

scaled DC = DC/Y₂₀ ^{Optimized powers}。

The basic principle behind this approach is: DC and Y₂₀Both depend on Hct and temperature, while only DC depends on the glucose concentration in the test sample. Thus, by adjusting with Y by a certain power₂₀By scaling the DC current, Hct and temperature dependence can be removed from the DC while glucose dependence is still preserved.

The power exponent is optimized by the pearson correlation score as shown in fig. 9-10. The power has been iterated between 0 and 10. DC3533 (DC current measured 3.533 seconds after the sample was adequate) was used in demonstrating the method. At each selected power, a pearson correlation is calculated between the scaled DC current and one of the three variables of interest (Hct (shown at Tarhct), temperature (shown as Condition _ T), and glucose concentration (shown as refglu _ PL). For example, when the power approaches 2, it can be observed that the pearson correlation score between the scaled DC current and the Tarhct approaches zero.

_conductorExample 4: and R scaling method.

The fourth scaling method is based on measuring at least two loop resistances of the biosensor electrode system and then normalizing each loop resistance to correct and/or compensate for electrode conductivity variations including conductive layer thickness variations. The basic principle behind this approach is: the loop resistance can and will vary, and non-uniform variations can affect the analyte concentration.

Referring again to fig. 2, the electrode system may include any number of different electrodes, including test meter contact pads and conductive trace portions, which thereby form a loop resistance. For example, one illustrated conductive path may include working electrode 121, working electrode contact pads 123a and 123b, and conductive trace portions 125a and 125b extending between working electrode 121 and working electrode contact pads 123a and 123b and electrically coupling working electrode 121 with working electrode contact pads 123a and 123 b. Another conductive path includes the counter electrode 120 (illustrated as including double teeth), the counter electrode contact pads 124a and 124b, and conductive trace portions 126a and 126b that extend between the counter electrode 120 and the counter electrode contact pads 124a and 124b and electrically couple the counter electrode 120 and the counter electrode contact pads 124a and 124 b.

FIG. 11 shows R measured at and without DC blocks obtained from samples having glucose concentrations of about 120mg/dL_conductorDifference in performance in case of scaling. The upper pane shows results from thirteen (13) different batches of material with different conductivities, where the calculated analyte concentrations varied significantly. In the bottom pane, R is applied_conductorAnd the variation is significantly reduced. In fig. 11, the y-axis is biased to the reference glucose concentration and the x-axis is the individual batches of biosensors.

All patents, patent applications, patent application publications, and other publications cited herein are hereby incorporated by reference as if set forth in their entirety.

The inventive concept has been described in connection with what is presently considered to be the most practical and preferred embodiment. The inventive concept has been presented by way of illustration, however, and is not intended to be limited to the disclosed embodiments. Accordingly, those skilled in the art will recognize that the inventive concept is intended to cover all modifications and alternative arrangements falling within the spirit and scope of the inventive concept as set forth in the appended claims. The numbered examples are presented below.

1. A method of scaling amperometric data obtained during electrochemical analysis of an analyte of interest to compensate for changes in electrode conductivity, the method comprising the steps of:

applying an electrical test sequence to a body fluid sample in an electrochemical biosensor, the biosensor comprising:

the electrode system is provided with a plurality of electrodes,

a reagent in electrical communication with the electrode system, and

a container configured to contact a liquid sample provided to the biosensor,

wherein the test sequence comprises at least one AC block, and at least one DC block of low amplitude signals, and wherein the bodily fluid sample comprises an analyte of interest;

measuring AC and DC current responses to electroactive species indicative of an analyte of interest;

measuring at least two loop resistances of an electrode system on the biosensor, wherein a first loop resistance is measured between two contact pads associated with the trace of the working electrode, and wherein a second loop resistance is measured between two contact pads associated with the trace of the counter electrode;

normalizing at least the two loop resistances (R) by dividing the first loop resistance by a first constant and by dividing the second loop resistance by a second constant_conductor) To obtain a normalized loop resistance;

the amperometric data is scaled by incorporating the smallest normalized loop resistance into an algorithm or fail-safe calculation for determining the analyte concentration.

2. The method of embodiment 1, wherein the AC block comprises a multi-frequency excitation waveform of at least two different frequencies.

3. The method of embodiment 2, wherein the frequencies are about 10kHz, about 20kHz, about 10kHz, about 2kHz, and about 1kHz, and each is applied for about 0.5sec to about 1.5 sec.

4. The method of embodiment 1, wherein the at least one DC block comprises at least one pulse to about ten pulses at a potential that alternates between about 0mV to about +450mV, and wherein each pulse is applied for about 50msec to about 500 msec.

5. The method of embodiment 4, wherein each DC pulse at about +450mV is applied for about 250msec and each DC pulse at about 0mV is applied for about 500 msec.

6. The method of embodiment 1, wherein the first constant and the second constant are predetermined median resistance values.

7. The method of embodiment 1, further comprising the step of estimating an analyte concentration based on the scaled amperometric data.

8. The method of embodiment 1, further comprising providing R_conductorA fail-safe step incorporated as a parameter into a fail-safe algorithm, wherein the fail-safe prevents reporting or displaying of the analyte concentration if the change in electrode conductivity is above a predetermined threshold.

9. The method of example 1, wherein the analyte concentration is a glucose concentration.

10. The method of embodiment 1, wherein the change in electrode conductivity is selected from the group consisting of a change in conductive layer thickness within the electrode system, a scratch within the electrode system, a defect within the electrode system, and a change in contact resistance between the biosensor contact pad and the meter contact.

11. An analyte concentration measurement device configured to perform the method of any one of claims 1-10.

12. The apparatus of embodiment 11, wherein the apparatus is a blood glucose meter.

13. An analyte concentration determination system configured to perform the method of any of embodiments 1-10.

14. The system of embodiment 13, wherein the system is a self-monitoring blood glucose (SMBG) system.

15. A method of scaling amperometric data obtained during an electrochemical analysis of an analyte of interest to compensate for hematocrit, the method comprising the steps of:

applying a test sequence comprising at least an AC block of low amplitude signals combined with at least one DC block to a bodily fluid sample, wherein the bodily fluid sample comprises an analyte of interest;

measuring AC and DC current responses to electroactive species indicative of an analyte of interest;

determining solution resistance (R) from AC current response information_solution) (ii) a And

by responding DC current to R_solutionThe amperometric data is scaled by multiplying to obtain a compensated voltage drop that minimizes the effect of hematocrit on the analyte concentration.

16. The method of embodiment 15, wherein the AC block comprises a multi-frequency excitation waveform of at least two different frequencies.

17. The method of embodiment 16, wherein the frequencies are about 10kHz, about 20kHz, about 10kHz, about 2kHz, and about 1kHz, and each is applied for about 0.5sec to about 1.5 sec.

18. The method of embodiment 15, wherein the at least one DC block comprises at least one pulse to about ten pulses at a potential alternating between about 0mV to about +450mV, and wherein each pulse is applied for about 50msec to about 500 msec.

19. The method of embodiment 18, wherein each DC pulse at about +450mV is applied for about 250msec and each DC pulse at about 0mV is applied for about 500 msec.

20. The method of embodiment 15 wherein R_solutionIs estimated from a linear fit of the x-intercept obtained by plotting the impedance of the current response to a block of low amplitude AC signals in a nyquist plot.

21. The method of embodiment 15, further comprising the step of estimating an analyte concentration based on the scaled amperometric data.

22. The method of embodiment 15, wherein the analyte concentration is a glucose concentration.

23. The method of embodiment 15, wherein scaling is based on a landls circuit model.

24. The method of embodiment 15, wherein the scaling uses a slope of the fitted impedance values and an angle with respect to an origin for the plurality of AC frequencies.

25. The method of any of embodiments 15-24, wherein the determining utilizes one or more descriptors of the scaled amperometric data.

26. The method of embodiment 25 wherein the descriptor is determined by subtracting R from the actual real impedance_solutionAnd then calculate a new impedance magnitude for each frequency.

27. The method of embodiment 26 wherein the new impedance magnitude is converted to an admittance (Y) magnitude and real and imaginary admittance values and corresponding new angles are calculated.

28. An analyte concentration measurement device configured to perform the method of any of embodiments 15-27.

29. The apparatus of embodiment 28, wherein the apparatus is a blood glucose meter.

30. An analyte concentration determination system configured to perform the method of any of embodiments 15-27.

31. The system of embodiment 30, wherein the system is a self-monitoring blood glucose (SMBG) system.

32. A method of scaling amperometric data obtained during electrochemical analysis of an analyte of interest to compensate for hematocrit and/or temperature, the method comprising the steps of:

applying a test sequence comprising an AC block and at least one DC block of low amplitude signals to a bodily fluid sample, wherein the bodily fluid sample comprises an analyte of interest;

measuring AC and DC current responses to electroactive species indicative of an analyte of interest; and

the amperometric data is scaled by calculating an admittance from the at least one AC current response and then dividing the DC current response by the admittance to obtain a compensated voltage that minimizes the effect of Hct and/or temperature on the analyte concentration.

33. The method of embodiment 32, wherein the AC block comprises a multi-frequency excitation waveform of at least two different frequencies.

34. The method of embodiment 33, wherein the frequencies are about 10kHz, about 20kHz, about 10kHz, about 2kHz, and about 1kHz, and each is applied for about 0.5sec to about 1.5 sec.

35. The method of embodiment 32, wherein the at least one DC block comprises at least one pulse to about ten pulses at a potential that alternates between about 0mV to about +450mV, and wherein each pulse is applied for about 50msec to about 500 msec.

36. The method of embodiment 35, wherein each DC pulse at approximately +450mV is applied for approximately 250msec and each DC pulse at approximately 0mV is applied for approximately 500 msec.

37. The method of embodiment 32, wherein the step of scaling comprises calculating a new angle (θ) formed between the selected DC current value and a corresponding admittance at the predetermined AC frequency, wherein the value of θ is calculated according to the following equation:

θ=arctan(DC/Y_{predetermined AC frequency}) And is and

wherein the predetermined AC frequency is 20 kHz.

38. The method of embodiment 32, further comprising the step of estimating an analyte concentration based on the scaled amperometric data.

39. The method of embodiment 32, wherein the analyte concentration is a glucose concentration.

40. An analyte concentration measurement device configured to perform the method of any of embodiments 32-39.

41. The apparatus of embodiment 40, wherein the apparatus is a blood glucose meter.

42. An analyte concentration determination system configured to perform the method of any of embodiments 32-39.

43. The system of embodiment 42, wherein the system is a self-monitoring blood glucose (SMBG) system.

44. A method of scaling amperometric data obtained during electrochemical analysis of an analyte of interest to compensate for hematocrit and/or temperature, the method comprising the steps of:

applying a test sequence comprising an AC block and at least one DC block of low amplitude signals to a bodily fluid sample, wherein the bodily fluid sample comprises an analyte of interest;

measuring AC and DC current responses to electroactive species indicative of an analyte of interest; and

the amperometric data is scaled by boosting the DC current response with an admittance (Y) from at least one of the AC current responses to obtain a compensated voltage that minimizes the effect of Hct and/or temperature on the analyte concentration.

45. The method of embodiment 44, wherein the AC block comprises a multi-frequency excitation waveform of at least two different frequencies.

46. The method of embodiment 45, wherein the frequencies are about 10kHz, about 20kHz, about 10kHz, about 2kHz, and about 1kHz, and each is applied for about 0.5sec to about 1.5 sec.

47. The method of embodiment 44, wherein the at least one DC block comprises at least one pulse to about ten pulses at a potential that alternates between about 0mV to about +450mV, and wherein each pulse is applied for about 50msec to about 500 msec.

48. The method of embodiment 47, wherein each DC pulse at approximately +450mV is applied for approximately 250msec and each DC pulse at approximately 0mV is applied for approximately 500 msec.

49. The method of embodiment 44, wherein the scaling is performed according to the following equation:

scaled DC = DC/Y^OP，

And wherein the scaled DC is a scaled DC value, DC is an unsealed DC value, Y is an admittance and OP is a power of optimization.

50. The method of embodiment 49, wherein the admittance (Y) corresponds to a 20kHz applied potential and the power exponent ranges from 0 to 10.

51. The method of embodiment 44, further comprising the step of estimating an analyte concentration based on the scaled amperometric data.

52. The method of embodiment 44, wherein the analyte concentration is a glucose concentration.

53. An analyte concentration measurement device configured to perform the method of any of embodiments 44-52.

54. The apparatus of embodiment 53, wherein the apparatus is a blood glucose meter.

55. An analyte concentration determination system configured to perform the method of any of embodiments 44-52.

56. The system of embodiment 55, wherein the system is a self-monitoring blood glucose (SMBG) system.

Claims (56)

1. A method of scaling amperometric data obtained during electrochemical analysis of an analyte of interest to compensate for changes in electrode conductivity, the method comprising the steps of:

applying an electrical test sequence to a body fluid sample in an electrochemical biosensor, the biosensor comprising:

the electrode system is provided with a plurality of electrodes,

a reagent in electrical communication with the electrode system, and

a container configured to contact a liquid sample provided to the biosensor,

wherein the test sequence comprises at least one AC block of low amplitude signals, and at least one DC block, and wherein the bodily fluid sample comprises an analyte of interest;

measuring AC and DC current responses to electroactive species indicative of an analyte of interest;

measuring at least two loop resistances of an electrode system of the biosensor, wherein a first loop resistance is measured between two contact pads associated with a trace of the working electrode, and wherein a second loop resistance is measured between two contact pads associated with a trace of the counter electrode;

normalizing the at least two loop resistances R by dividing the first loop resistance by a first constant and by dividing the second loop resistance by a second constant_conductorTo obtain a normalized loop resistance;

the amperometric data is scaled by incorporating the smallest normalized loop resistance into an algorithm or fail-safe calculation for determining the analyte concentration.

2. The method of claim 1, wherein the AC block comprises a multi-frequency excitation waveform of at least two different frequencies.

3. The method of claim 2, wherein the multi-frequency excitation waveform comprises five segments, wherein the frequencies of the segments are 10kHz, 20kHz, 10kHz, 2kHz, and 1kHz, and wherein each is applied for 0.5sec to 1.5 sec.

4. The method of any of claims 1 to 3, wherein the at least one DC block comprises at least one pulse to ten pulses at a potential that alternates between 0mV to +450mV, and wherein each pulse is applied for 50msec to 500 msec.

5. The method of claim 4, wherein each DC pulse at +450mV is applied for 250msec and each DC pulse at 0mV is applied for 500 msec.

6. The method of any of claims 1 to 3, wherein the first constant and the second constant are predetermined median resistance values.

7. The method of any one of claims 1 to 3, further comprising the step of estimating the analyte concentration based on the scaled amperometric data.

8. The method of any one of claims 1 to 3, further comprising providing R_conductorA fail-safe step incorporated as a parameter into a fail-safe algorithm, wherein the fail-safe prevents reporting or displaying of the analyte concentration if the change in electrode conductivity is above a predetermined threshold.

9. The method of any one of claims 1 to 3, wherein the analyte concentration is a glucose concentration.

10. The method of any one of claims 1 to 3, wherein the change in electrode conductivity is selected from the group consisting of a change in conductive layer thickness within the electrode system, a scratch within the electrode system, a defect within the electrode system, and a change in contact resistance between the biosensor contact pad and the meter contact.

11. An analyte concentration measurement device configured to perform the method of any one of claims 1 to 10.

12. The device of claim 11, wherein the device is a blood glucose meter.

13. An analyte concentration determination system configured to perform the method of any one of claims 1 to 10.

14. The system of claim 13, wherein the system is a self-monitoring blood glucose SMBG system.

15. A method of scaling amperometric data obtained during an electrochemical analysis of an analyte of interest to compensate for hematocrit, the method comprising the steps of:

applying a test sequence comprising at least an AC block of low amplitude signals combined with at least one DC block to a bodily fluid sample, wherein the bodily fluid sample comprises an analyte of interest;

measuring AC and DC current responses to electroactive species indicative of an analyte of interest;

determining solution resistance R from AC current response information_solution(ii) a And

by responding DC current to R_solutionThe amperometric data is scaled by multiplying to obtain a compensated voltage drop that minimizes the effect of hematocrit on the analyte concentration.

16. The method of claim 15, wherein the AC block comprises a multi-frequency excitation waveform of at least two different frequencies.

17. The method of claim 16, wherein the multi-frequency excitation waveform comprises five segments, wherein the frequencies of the segments are 10kHz, 20kHz, 10kHz, 2kHz, and 1kHz, and wherein each is applied for 0.5sec to 1.5 sec.

18. The method of any of claims 15 to 17, wherein the at least one DC block comprises at least one pulse to ten pulses at a potential that alternates between 0mV to +450mV, and wherein each pulse is applied for 50msec to 500 msec.

19. The method of claim 18, wherein each DC pulse at +450mV is applied for 250msec and each DC pulse at 0mV is applied for 500 msec.

20. The method of any one of claims 15 to 17, wherein R_solutionIs estimated from a linear fit of the x-intercept obtained by plotting the impedance of the current response to a block of low amplitude AC signals in a nyquist plot.

21. The method of any one of claims 15 to 17, further comprising the step of estimating the analyte concentration based on the scaled amperometric data.

22. The method of any one of claims 15 to 17, wherein the analyte concentration is a glucose concentration.

23. The method of any one of claims 15 to 17, wherein the scaling is based on a landls circuit model.

24. The method of any of claims 15 to 17, wherein the scaling uses a slope of the fitted impedance values and an angle with respect to an origin for a plurality of AC frequencies.

25. The method of any of claims 15 to 17, wherein the determining utilizes one or more descriptors of the scaled amperometric data.

26. The method of claim 25, wherein the descriptor is generated by subtracting R from the actual real impedance_solutionAnd then calculate a new impedance magnitude for each frequency.

27. The method of claim 26, wherein the new impedance magnitude is converted to an admittance Y magnitude, and real and imaginary admittance values and corresponding new angles are calculated.

28. An analyte concentration measurement apparatus configured to perform the method of any one of claims 15 to 27.

29. The device of claim 28, wherein the device is a blood glucose meter.

30. An analyte concentration determination system configured to perform the method of any one of claims 15 to 27.

31. The system of claim 30, wherein the system is a self-monitoring blood glucose SMBG system.

32. A method of scaling amperometric data obtained during electrochemical analysis of an analyte of interest to compensate for hematocrit and/or temperature, the method comprising the steps of:

applying a test sequence comprising an AC block of low amplitude signals and at least one DC block to a bodily fluid sample, wherein the bodily fluid sample comprises an analyte of interest;

measuring AC and DC current responses to electroactive species indicative of an analyte of interest; and

the amperometric data is scaled by calculating an admittance from the at least one AC current response and then dividing the DC current response by the admittance to obtain a compensated voltage that minimizes the effect of Hct and/or temperature on the analyte concentration.

33. The method of claim 32, wherein the AC block comprises a multi-frequency excitation waveform of at least two different frequencies.

34. The method of claim 33, wherein the multi-frequency excitation waveform comprises five segments, wherein the frequencies of the segments are 10kHz, 20kHz, 10kHz, 2kHz, and 1kHz, and wherein each is applied for 0.5sec to 1.5 sec.

35. The method of any of claims 32 to 34, wherein the at least one DC block comprises at least one pulse to ten pulses at a potential that alternates between 0mV to +450mV, and wherein each pulse is applied for 50msec to 500 msec.

36. The method of claim 35, wherein each DC pulse at +450mV is applied for 250msec and each DC pulse at 0mV is applied for 500 msec.

37. The method of any of claims 32 to 34, wherein the scaling step comprises calculating a new angle θ formed between the selected DC current value and the corresponding admittance at the predetermined AC frequency, wherein the value of θ is calculated according to the following equation:

θ=arctan(DC/Y_{predetermined AC frequency}) And is and

wherein the predetermined AC frequency is 20 kHz.

38. The method of any one of claims 32 to 34, further comprising the step of estimating the analyte concentration based on the scaled amperometric data.

39. The method of any one of claims 32 to 34, wherein the analyte concentration is a glucose concentration.

40. An analyte concentration measurement device configured to perform the method of any one of claims 32 to 39.

41. The device of claim 40, wherein said device is a blood glucose meter.

42. An analyte concentration determination system configured to perform the method of any one of claims 32 to 39.

43. The system of claim 42, wherein the system is a self-monitoring blood glucose SMBG system.

44. A method of scaling amperometric data obtained during electrochemical analysis of an analyte of interest to compensate for hematocrit and/or temperature, the method comprising the steps of:

applying a test sequence comprising an AC block of low amplitude signals and at least one DC block to a bodily fluid sample, wherein the bodily fluid sample comprises an analyte of interest;

measuring AC and DC current responses to electroactive species indicative of an analyte of interest; and

the amperometric data is scaled by boosting the DC current response with an admittance Y from at least one of the AC current responses to obtain a compensated voltage that minimizes the effect of Hct and/or temperature on the analyte concentration.

45. The method of claim 44, wherein the AC block includes a multi-frequency excitation waveform of at least two different frequencies.

46. The method of claim 45, wherein the multi-frequency excitation waveform includes five segments, wherein the frequencies of the segments are 10kHz, 20kHz, 10kHz, 2kHz, and 1kHz, and wherein each is applied for 0.5sec to 1.5 sec.

47. The method of any of claims 44 to 46, wherein the at least one DC block includes at least one pulse to ten pulses at a potential that alternates between 0mV to +450mV, and wherein each pulse is applied for 50msec to 500 msec.

48. The method of claim 47, wherein each DC pulse at +450mV is applied for 250msec and each DC pulse at 0mV is applied for 500 msec.

49. The method of any of claims 44 to 46, wherein the scaling is performed according to the following equation:

scaled DC = DC/Y^OP，

And wherein the scaled DC is a scaled DC value, DC is an unsealed DC value, Y is an admittance and OP is a power of optimization.

50. The method of claim 49, wherein the admittance Y corresponds to an applied potential of 20kHz and the power exponent ranges from 0 to 10.

51. The method of any one of claims 44 to 46, further comprising the step of estimating the analyte concentration based on the scaled amperometric data.

52. The method of any one of claims 44 to 46, wherein the analyte concentration is a glucose concentration.

53. An analyte concentration measurement device configured to perform the method of any one of claims 44 to 52.

54. The device of claim 53, wherein said device is a blood glucose meter.

55. An analyte concentration determination system configured to perform the method of any one of claims 44 to 52.

56. The system of claim 55, wherein the system is a self-monitoring blood glucose SMBG system.