Source: http://www.patentgenius.com/patent/8709739.html
Timestamp: 2018-02-18 05:30:53
Document Index: 270922645

Matched Legal Cases: ['Application No. 08', 'Application No. 10', 'Application No. 10', 'Application No. 200910134602', 'Application No. 2009', 'Application No. 2011', 'Application No. 07251388', 'Application No. 2648625', 'application No. 2007201377', 'application No. 2582643', 'application No. 2582643', 'application No. 07251388', 'application No. 2008221593', 'application No. 2639776', 'application No. 2009200097', 'application No. 2011201199', 'application No. 2008221593', 'Application No. 2009202200', 'Application No. 2007201377']

System and method for measuring an analyte in a sample - Patent # 8709739 - PatentGenius
8709739 System and method for measuring an analyte in a sample
U.S. Class: 435/14; 204/403.01; 205/777.5; 600/347; 600/365
Field Of Search: ;205/777.5; ;205/778; ;205/792; ;204/403.01; ;435/14; ;435/25; ;436/70; ;600/347; ;600/365
Foreign Patent Documents: 3104293; 5487394; 2007201377; 2009200097; 2009202200; 2748433; 2582643; 1338049; 1692277; 3103464; 0171375; 0172969; 0251915; 0255291; 0266204; 0278647; 0290770; 0299779; 0351516; 0351891; 0351892; 0359831; 0400918; 0418404; 0451981; 0560336; 0800086; 1 042 667; 1 156 324; 1156324; 1172649; 1 281 960; 1281960; 1 394 545; 1447452; 1557662; 1 840 219; 1839571; 1839571; 1840219; 1840219; 2098857; 2267149; 2076168; 2 482 069; 2020424; 2154735; 2201248; 2235050; 3099254; 3167464; 4066112; 4343065; 5002007; 6222874; 11230934; 2001-066274; 200166274; 2001153839; 2003114214; 2003-185615; 2003521708; 2003240747; 2003-262604; 2004245836; 2005147990; 2007087710; 2007108171; 2007133985; 2007522449; 2007225619; 2007248281; 2007271623; 2007531877; 2009528540; 2009-536744; 1351627; WO-8908713; WO-9215701; WO-9402842; WO-9516198; WO-9700441; WO-9718465; WO-0020626; 01/40787; 0157510; WO-0157510; 2004040286; WO2004113913; WO2005066355; 2005098424; WO 2006/110504; WO-2006110504; WO2006109277; 2007/133985; 2007130907; WO 2008/004565
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Abstract: Methods of determining a corrected analyte concentration in view of some error source are provided herein. The methods can be utilized for the determination of various analytes and/or various sources of error. In one example, the method can be configured to determine a corrected glucose concentration in view of an extreme level of hematocrit found within the sample. In other embodiments, methods are provided for identifying various system errors and/or defects. For example, such errors can include partial-fill or double-fill situations, high track resistance, and/or sample leakage. Systems are also provided for determining a corrected analyte concentration and/or detecting some system error.
1. A system for determining a corrected glucose concentration of a sample, comprising: an electrochemical cell having at least two electrodes including a firstelectrode and a second electrode, the electrochemical cell being sized and configured to receive the sample, the electrochemical cell further configured to determine an initial glucose concentration and also configured to generate a pre-determinedvoltage between the first and second electrodes for a pre-determined amount of time, and further configured to measure at least one resulting current of the sample during the pre-determined time; and a processor programmed for receiving a set of datafrom the electrochemical cell, the data including the initial glucose concentration, at least one applied voltage, and at least one resulting current, the processor further programmed to utilize this data to determine a corrected glucose concentration,said electrochemical cell being further configured to measure a hematocrit level of the sample, and in which the processor receives and utilizes the measured hematocrit level to determine a correction term based on the measured hematocrit level and theinitial glucose concentration, the processor being further programmed to utilize the correction term as data in determining the corrected glucose concentration.
2. The system of claim 1, wherein the processor utilizes a set of equations to determine the correction term depending on the measured hematocrit level and the initial glucose concentration.
3. The system of claim 2, wherein an equation of the set of equations utilized by the processor is selected to calculate the corrected glucose concentration based on at least one of: a comparison of the measured hematocrit level to one or morepredetermined hematocrit levels and a comparison of the initial glucose concentration to one or more predetermined glucose concentration levels.
4. The system of claim 2, wherein the processor is programmed to calculate the correction term Corr using a first function, the first function being utilized if the hematocrit level H is less than a lower predetermined hematocrit level H.sub.Land if the initial glucose concentration G.sub.1 is less than an upper predetermined glucose concentration value G.sub.U.
5. The system of claim 4, wherein the first function is one of the set of equations, the equation being Corr=K.sub.1(H.sub.L-H)G.sub.1 where Corr is the correction value, K.sub.1 is a first constant, H.sub.L is the lower predeterminedhematocrit level, H is the hematocrit level, and G.sub.1 is the initial glucose concentration.
6. The system of claim 5, wherein the corrected glucose concentration G.sub.2 is determined by the equation G.sub.2=G.sub.1+Corr if the initial glucose concentration G.sub.1 is less than a glucose threshold.
7. The system of claim 5, wherein the corrected glucose concentration G.sub.2 is determined by the equation .function. ##EQU00012## if the initial glucose concentration G.sub.1 is greater than a glucose threshold.
8. The system of claim 2, wherein the processor is programmed to calculate the correction value Corr using a second function, the second function being utilized if the hematocrit level H is less than a lower predetermined hematocrit levelH.sub.L and if the initial glucose concentration G.sub.1 is greater than an upper predetermined glucose concentration value G.sub.U.
9. The system of claim 8, wherein the second function is one of the set of equations, the equation being Corr=K.sub.2(H.sub.L-H)(G.sub.max-G.sub.1) where Corr is the correction value, K.sub.2 is a second constant, H.sub.L is the lowerpredetermined hematocrit level, H is the hematocrit level, G.sub.max is a predetermined maximum glucose concentration, and G.sub.1 is the initial glucose concentration.
10. The system of claim 1, wherein the corrected glucose concentration G.sub.2 is determined to be substantially equal to the initial glucose concentration G.sub.1 if the hematocrit level H is greater than an upper predetermined hematocritlevel H.sub.U and if the first glucose concentration G.sub.1 is less than a lower predetermined glucose concentration G.sub.L.
11. The system of claim 2, wherein the processor is programmed to calculate the correction value Corr using a utilized third function if the measured hematocrit level H is greater than an upper predetermined hematocrit level H.sub.U and if theinitial glucose concentration G.sub.1 is greater than the lower predetermined glucose concentration G.sub.L.
12. The system of claim 11, wherein the third function is one of the set of equations, the equation being Corr=K.sub.4(H-H.sub.U)(G.sub.1-G.sub.L) where Corr is the correction value, K.sub.4 is a fourth constant, H is the hematocrit level,H.sub.U is the upper predetermined hematocrit level, G.sub.1 is the initial glucose concentration, and G.sub.L is the lower predetermined glucose concentration.
13. The system of claim 1, wherein the hematocrit level H is based on at least one resulting current determined during a first time interval T.sub.1 and a second time interval T.sub.2.
14. The system of claim 1, wherein the first electrode and the second electrode have an opposing face arrangement.
Analyte detection in physiological fluids, e.g. blood or blood derived products, is of ever increasing importance to today's society. Analyte detection assays find use in a variety of applications, including clinical laboratory testing, hometesting, etc., where the results of such testing play a prominent role in diagnosis and management of a variety of disease conditions. Analytes of interest include glucose for diabetes management, cholesterol, and the like. In response to this growingimportance of analyte detection, a variety of analyte detection protocols and devices for both clinical and home use have been developed.
One type of method that is employed for analyte detection is an electrochemical method. In such methods, an aqueous liquid sample is placed into a sample-receiving chamber in an electrochemical cell that includes at least two electrodes, e.g.,a counter electrode and a working electrode. The analyte is allowed to react with a redox reagent to form an oxidizable (or reducible) substance in an amount corresponding to the analyte concentration. The quantity of the oxidizable (or reducible)substance present is then estimated electrochemically and related to the amount of analyte present in the initial sample.
Such systems are susceptible to various modes of inefficiency and/or error. For example, where the physiological sample being assayed is whole blood or a derivative thereof, the hematocrit of the sample can be a source of analytical error inthe ultimate analyte concentration measurement. Thus, in electrochemical measurement protocols where the analyte concentration is derived from observed time-current transients, increased hematocrit levels can increase the sample viscosity, which inturn, can slow the diffusion of enzyme, analyte, and mediator, thereby attenuating the test current and causing analytical error. Additionally, a partial fill or a double-fill of a sample-receiving chamber, a defective test strip, and/or leakage ofsample can result in incorrect and/or inefficient testing.
Various aspects of a method of calculating a corrected analyte concentration of a sample are provided. That is, the methods typically include making an initial analyte determination, determining a correction factor based on various systemmeasurements and/or parameters, and modifying the initial analyte concentration based on the correction factor thereby overcoming some source of error. For example, the analyte can be glucose and the error source can be an increased hematocrit levelwhich if not accounted for could result in an incorrect reading. Other methods account for various system errors such as double-dosing events, maximum current check, minimum current check, high resistance track, and/or leakage. While the methodsprovided below are focused on the detection of glucose, various other protocols are within the spirit and scope of the disclosure. For example, the method can be utilized for the detection or measurement of lactate, cholesterol, hemoglobin or totalantioxidants.
In use, the methods are performed with an electrochemical cell which is sized and configured to receive a sample (e.g., blood). The electrochemical cell typically includes at least two electrodes configured so that they are closely spaced andcan be wetted by a small volume of liquid. The various methods are capable of determining an accurate analyte concentration in view of some error source or determining some system error by determining various current readings during one or many appliedvoltages, determining a correction factor from the various readings, and using this correction factor to determine a corrected analyte concentration. The electrochemical cell is used in conjunction with a meter. An electrical power source, for examplea battery, in the meter is used to apply a voltage or a series of voltages across the electrodes of the electrochemical cell thereby causing an electrical current to flow. The current flowing is measured by electronic circuitry in the meter as afunction of time and the current measurements can be used to derive a concentration of the analyte of interest.
The methods provided herein typically involve applying various test voltages for certain pre-determined time periods, measuring test currents present during those time periods, and utilizing these measurements to determine an initial analyteconcentration, a correction factor, an error source, and a corrected analyte concentration. For example, the method can include providing a sample (e.g., blood) with an unknown glucose concentration to an electrochemical cell and applying a first testvoltage V.sub.1 for a first time interval T.sub.1 between a first electrode and a second electrode sufficient to oxidize a reduced mediator at the second electrode. Additionally, the method can include applying a second test voltage V.sub.2 for a secondtime interval T.sub.2 between the first electrode and the second electrode sufficient to oxidize the reduced mediator at the first electrode where the first test voltage V.sub.1 is applied before the second test voltage V.sub.2. In this example, themethod can include calculating a initial glucose concentration G.sub.1 based on test current values during the first time interval T.sub.1 and the second time interval T.sub.2, calculating an error source, in this case an increased hematocrit level H,and calculating a corrected glucose concentration G.sub.2 based on the initial glucose concentration G.sub.1 and the hematocrit level H.
In one embodiment, the step of calculating the corrected glucose concentration includes calculating a correction value Corr with a first function if the hematocrit level H is less than a lower predetermined hematocrit level H.sub.L (e.g., about30%) and if the initial glucose concentration G.sub.1 is less than an upper predetermined glucose concentration G.sub.U (e.g., about 300 mg/dL). For example, the first function can be an equation Corr=K.sub.1(H.sub.L-H) G.sub.1 where Corr is thecorrection value, K.sub.1 is a first constant (e.g., about -0.004), H.sub.L is the lower predetermined hematocrit level (e.g., about 30%), H is the hematocrit level, and G.sub.1 is the initial glucose concentration. The various constants in theequations are typically derived empirically, where a set of test results are obtained with the measurement system using whole blood with different hematocrit and glucose concentrations spanning the range of interest. Typically, nonlinear least squaresfitting procedure is then used, where the constants that give the smallest overall difference between the value of the parameter of interest derived from the current data, and the actual value of the parameter are determined. The parameter of interestdepends at least in part on the constants being determined. For example, if the constants formed part of an equation which estimated the hematocrit of the sample, then the sample hematocrit would be the parameter of interest. In the case of theconstants in the equation for Corr given above, the parameter of interest is the concentration of glucose in the blood. Those skilled in the art will appreciate that various other statistical analysis methods can be utilized to provide values for theconstants.
The correction factor can be determined if the hematocrit level and the initial glucose concentration fall within other ranges. For example, the step of calculating the second glucose concentration includes calculating a correction value Corrwith a second function if the hematocrit H is less than a lower predetermined hematocrit level H.sub.L (e.g., about 30%) and if the initial glucose concentration G.sub.1 is greater than the upper predetermined glucose concentration G.sub.U (e.g., about300 mg/dL). In such an embodiment, the method can also include calculating a corrected glucose concentration G.sub.2 based on the initial glucose concentration G.sub.1, the hematocrit level H, and the correction value Corr. Additionally, the secondfunction can be an equation such as Corr=K.sub.2(H.sub.L-H)(G.sub.max-G.sub.1) where Corr is the correction value, K.sub.2 is a second constant (e.g., -0.004), H.sub.L is the lower predetermined hematocrit level (e.g., about 30%), H is the hematocritlevel, G.sub.max is a predetermined maximum glucose concentration (e.g., about 600 mg/dL), and G.sub.1 is the first glucose concentration.
In certain circumstances, the method can also assign and utilize a correction value Corr equal to zero. For example, in one embodiment, the corrected glucose concentration G.sub.2 can be substantially equal to the initial glucose concentrationG.sub.1 (i.e., Corr=0) if the hematocrit level H is greater than an upper predetermined hematocrit level H.sub.U (e.g., about 50%) and if the initial glucose concentration G.sub.1 is less than a lower predetermined glucose concentration G.sub.L (e.g.,about 100 mg/dL) or the hematocrit level H is less than an upper predetermined hematocrit level H.sub.U (e.g., about 50%) and greater than a lower predetermined hematocrit level H.sub.L (e.g., about 30%).
In one embodiment, the step of calculating the second glucose concentration G.sub.2 includes calculating a correction value Corr with a fourth function if the hematocrit level H is greater than an upper predetermined hematocrit level H.sub.U(e.g., about 50%) and if the initial glucose concentration G.sub.1 is greater than the lower predetermined glucose concentration G.sub.L (e.g., about 100 mg/dL). In such an embodiment, the method can also include calculating a corrected glucoseconcentration G.sub.2 based on the initial glucose concentration G.sub.1, the hematocrit level H, and the correction value Corr. Additionally, the fourth function can be an equation such as Corr=K.sub.4(H-H.sub.U)(G.sub.1-G.sub.L) where Corr equals thecorrection value, K.sub.4 is a fourth constant (e.g., 0.011), H is the hematocrit level, H.sub.U is the upper predetermined hematocrit level (e.g., about 50%), G.sub.1 is the initial glucose concentration, and G.sub.L is the lower predetermined glucoseconcentration (e.g., about 100 mg/dL).
Various correction equations can be utilized to find a value for the corrected glucose concentration G.sub.2. For example, in some embodiments, the correction equation can be selected based on the initial glucose concentration relative to someglucose threshold. That is, the method can include the step of calculating the corrected glucose concentration G.sub.2 using a correction equation in those cases where the initial glucose concentration G.sub.1 is less than a glucose threshold with thecorrection equation being G.sub.2=G.sub.1+Corr. Also, the method can include the step of calculating the corrected glucose concentration G.sub.2 using a correction equation if the initial glucose concentration G.sub.1 is greater than a glucose thresholdwherein this correction equation is
As will be apparent to those skilled in the art, any number and magnitude of test voltages can be supplied to the sample at any number or pattern of time intervals. For example, in one embodiment, the second test voltage V.sub.2 can be appliedimmediately after the first test voltage V.sub.1. Also, the first test voltage V.sub.1 can have a first polarity and the second test voltage V.sub.2 has a second polarity wherein the first polarity is opposite in magnitude or sign to the secondpolarity. As indicated, the first and second test voltage can be of virtually any amount capable of providing the desired effect. For example, in one embodiment, the first test voltage V.sub.1 can range from about -100 mV to about -600 mV with respectto the second electrode, and the second test voltage V.sub.2 can range from about +100 mV to about +600 mV with respect to the second electrode. Additionally, the method can further include applying a third test voltage V.sub.3 for a third time intervalT.sub.3 between the first electrode and the second electrode where the absolute magnitude of the resulting test current is substantially less than the absolute magnitude of the resulting test current for the second test voltage V.sub.2. The third testvoltage can be applied before the first test voltage V.sub.1 or at any other time interval (e.g., after the second test voltage) as desired. Additionally, various arrangement and/or configurations of electrodes are included herein. For example, in anexemplary embodiment, the first electrode and the second electrode can have an opposing face arrangement. Additionally, a reagent layer can be disposed on the first electrode.
The method also provides various manners of measuring a patient's hematocrit level. For example, the hematocrit level H can be based on test current values during the first time interval T.sub.1 and the second time interval T.sub.2. In anexemplary embodiment, the hematocrit level H can be calculated using a hematocrit equation. For example, the hematocrit equation can be H=K.sub.5 ln(|i.sub.2|)+K.sub.6 ln(G.sub.1)+K.sub.7 where H is the hematocrit level, K.sub.5 is a fifth constant(e.g., -76.001), i.sub.2 is at least one current value during the second time interval, K.sub.6 is a sixth constant (e.g., 56.024), G.sub.1 is the initial glucose concentration, and K.sub.7 is a seventh constant (e.g., 250).
In another aspect, a method of calculating an analyte concentration is provided which includes applying a first test voltage V.sub.1 for a first time interval T.sub.1 between a first electrode and a second electrode sufficient to oxidize areduced mediator at the second electrode, and applying a second test voltage V.sub.2 for a second time interval T.sub.2 between the first electrode and the second electrode sufficient to oxidize the reduced mediator at the first electrode. The methodalso includes calculating an initial glucose concentration G.sub.1 based on test current values during the first time interval T.sub.1 and the second time interval T.sub.2. The method further includes calculating a hematocrit level H, and applying afirst function to calculate the corrected glucose concentration if the initial glucose concentration G.sub.1 is less than an upper predetermined glucose concentration G.sub.U and the hematocrit level is less than a lower predetermined hematocrit levelH.sub.L. The method also includes applying a second function to calculate the corrected glucose concentration if the initial glucose concentration G.sub.1 is greater than an upper predetermined glucose concentration G.sub.U and the hematocrit level isless than a lower predetermined hematocrit level H.sub.L, applying a third function to calculate the corrected glucose concentration if the initial glucose concentration G.sub.1 is less than a lower predetermined glucose concentration G.sub.L and thehematocrit level is greater than an upper predetermined hematocrit level H.sub.U, and applying a fourth function to calculate the corrected glucose concentration if the initial glucose concentration G.sub.1 is greater than a lower predetermined glucoseconcentration G.sub.L and the hematocrit level is greater than an upper predetermined hematocrit level H.sub.U.
The various functions can include various equations. For example, the first function can include an equation such as Corr=K.sub.1(H.sub.L-H) G.sub.1 where Corr is the correction value, K.sub.1 is a first constant (e.g., -0.004), H.sub.L is thelower predetermined hematocrit level (e.g., about 30%), H is the hematocrit level, and G.sub.1 is the initial glucose concentration. The second function can include an equation such as Corr=K.sub.2(H.sub.L-H) (G.sub.max-G.sub.1) where Corr is thecorrection value, K.sub.2 is a second constant (e.g., -0.004), H.sub.L is the lower predetermined hematocrit level (e.g., about 30%), H is the hematocrit level, G.sub.max is a predetermined maximum glucose concentration (e.g., about 600 mg/dL), andG.sub.1 is the initial glucose concentration. The third function can includes an equation such as Corr=0 where Corr is the correction value, and the fourth function can include an equation such as Corr=K.sub.4(H-H.sub.U)(G.sub.1-G.sub.L) where Corr isthe correction value, K.sub.4 is a fourth constant (e.g., 0.011), H is the hematocrit level, H.sub.U is the upper predetermined hematocrit level (e.g., about 50%), G.sub.1 is the initial glucose concentration, G.sub.L is the lower predetermined glucoseconcentration (e.g., about 100 mg/dL).
Additionally, the various correction values can be utilized with various embodiments of a correction equation configured to provide an adjusted analyte value. For example, the method can include the step of calculating the corrected glucoseconcentration G.sub.2 with a correction equation if the initial glucose concentration G.sub.1 is less than a glucose threshold wherein the correction equation is G.sub.2=G.sub.1+Corr. The method can also include the step of calculating the correctedglucose concentration G.sub.2 with a correction equation if the initial glucose concentration G.sub.1 is greater than a glucose threshold, the correction equation being
In one embodiment, the method can also include applying a third test voltage V.sub.3 for a third time interval T.sub.3 between the first electrode and the second electrode where the absolute magnitude of the resulting test current issubstantially less than the absolute magnitude of the resulting test current for the second test voltage V.sub.2. In such an embodiment, the third test voltage V.sub.3 can be applied before the first test voltage V.sub.1. In such an embodiment, thethird test voltage V.sub.3 is of a magnitude that results in a test current that is substantially less than the absolute magnitude of the resulting test current for the second test voltage V.sub.2 to minimize interference with the currents that aremeasured during the application of V.sub.1 and V.sub.2. The smaller current flowing during the application of V.sub.3 means a smaller amount of redox species is electrochemically reacted at the electrodes so less disruption of the concentration profilesof the redox species in the electrochemical cell will be caused by the application of V.sub.3.
Various embodiments of a method of identifying a defect (e.g., high track resistance) in a test strip are also provided. In one such aspect, a method is provided which includes applying a first test voltage for a first test time intervalbetween a first electrode and a second electrode sufficient to oxidize a reduced mediator at the second electrode, and applying a second test voltage for a second test time interval between a first electrode and a second electrode sufficient to oxidize areduced mediator at the first electrode. Alternatively, only a first test voltage applied for a first time interval is required to practice the method. The method can also include measuring a first test current and a second test current that occurduring the first or second test time interval wherein the second test current occurs after the first test current during the same test time interval, and determining whether the test strip has the defect using an equation based on the first test current,and the second test current. In an exemplary embodiment, the second test voltage can be applied immediately after the first test voltage.
Various embodiments of such an equation are provided herein. For example, the equation can include a ratio between the first test current and the second test current. Additionally, the equation can include a ratio between the first testcurrent and the difference between the first test current and the second test current. In one embodiment, the first test current can occur at about a beginning of the first or second test time interval, and the first test current can be a maximumcurrent value occurring during the first or second test time interval. Also, the second test current can occur at about an end of the first or second test time interval, and the second test current is a minimum current value occurring during the firstor second test time interval. In one example, the equation can be a
##EQU00003## where i.sub.1 is the first test current and i.sub.2 is the second test current. In use, the method can include a step of providing an error message indicating a defective test strip if the ratio is greater than a firstpredetermined threshold (e.g., about 1.2).
Similar to above, various arrangements and/or configurations of electrodes are included within the spirit and scope of the present disclosure. For example, a polarity of the first test voltage is opposite to a polarity of the second testvoltage. Also, the first electrode and second electrode have an opposing face arrangement. Additionally, the first voltage and/or the second voltage can be any of a wide range of voltages. For example, the first test voltage can range from about zeroto about -600 mV with respect to the second electrode, and the second test voltage can range from about 10 mV to about 600 mV with respect to the second electrode.
As indicated, one such defect to be identified by an embodiment of the method can be a high track resistance. For example the high track resistance can be between an electrode connector and the electrodes in the electrochemical cell. Thefunction of the tracks is to provide an electrically conductive path between the connection points on the meter and the electrodes in the electrochemical cell. While current is flowing down these tracks some of the voltage applied by the meter will bedissipated along the tracks according to Ohm's Law, with the higher the electrical resistance and current flow down the track the greater the voltage drop. In this embodiment, the method is based upon the current flowing between the electrodes at shorttimes after the application of a voltage being larger than the current flowing at longer times, due to the initially higher concentration of reduced mediator close to the electrode at short times. If the track resistance is too high, while current isflowing the voltage drop that occurs along the tracks will be greater than desired when the larger initial currents are attempting to flow. This larger than desired voltage drop will result in insufficient voltage being applied between the electrodes inthe electrochemical cell, which in turn will cause a lower current to flow than would be the case if there was acceptable track resistance. According to this embodiment, the lower than expected current flowing at short times is detected by comparing itby the methods disclosed above to the current flowing at longer times, which naturally being lower is not so affected by the high track resistance.
In another aspect, a method of identifying a defect (e.g., leakage) in a test strip is provided. Such methods can include applying a first test voltage for a first test time interval between a first electrode and a second electrode sufficientto oxidize a reduced mediator at the second electrode, and applying a second test voltage for a second test time interval between a first electrode and a second electrode sufficient to oxidize a reduced mediator at the first electrode. The method alsoincludes measuring a first test current, a second test current, a third test current, and a fourth test current that occur during the second test time interval, calculating a first logarithm of a first ratio based on the first test current and the secondtest current, calculating a second logarithm of a second ratio based on the third test current and the fourth test current, and determining whether the test strip has a defect using an equation based on the first logarithm and the second logarithm. Inan exemplary embodiment, the defect is a leakage of fluid between a spacer and the first electrode. In some embodiments, a reagent layer can be disposed on the first electrode so that a portion of the reagent layer can be between the spacer and thefirst electrode.
.function..function. ##EQU00004## where i.sub.1 is the first test current i.sub.2, is the second test current, i.sub.3 is the third test current, and i.sub.4 is the fourth test current. In use, the method can further include a step ofproviding an error message indicating a defective test strip if the third ratio is less than a predetermined threshold (e.g., about 1, about 0.95, etc.).
In one embodiment, the first test current and the second test current can be the two largest current values during the second time interval. In one embodiment, the fourth test current can be a smallest current value occurring during the secondtime interval. Also, in one embodiment, a difference between a fourth test current time and a third test current time is greater than a difference between a second test current time and a first test current time. In this embodiment, the method includescomparing the shape of the current versus time profile, as embodied by the i.sub.1, i.sub.2, i.sub.3, and i.sub.4 measured currents, to an expected shape, as embodied by the predetermined threshold, in order to make a judgment or determination as towhether the shape of the current transient is acceptable.
Additionally, various aspects of a method of identifying an error in performing a test with a test strip are provided herein. In one such aspect, the method includes applying a test voltage for a test time interval between a first electrode anda second electrode, measuring consecutively a first test current, a second test current, and a third test current, and determining whether an error was performed by using an equation based on the second test current and a summation of the absolute valueof the first test current and the absolute value of the third test current. Various time differences between measurements can be utilized. For example, a time difference between the measurements of the first test current and the second test current canrange from about one nanosecond to about 100 milliseconds. Also, a time difference between the measurements of the first test current and the third test current can range from about one nanosecond to about 100 milliseconds.
Similar to above, various embodiments of the equation are provided herein. For example, in an exemplary embodiment the equation is Y=2*abs(i(t))-abs(i(t-x))-abs(i(t+x)), where i(t) is the second test current, i(t-x) is the first test current,i(t+x) is the third test current, t is a time, and x is an increment of time, and abs represents an absolute function. In one embodiment, the equation is Z=abs(i(t+x))-abs(i(t)), where i(t) is the second test current, i(t+x) is the third test current, tis a time, and x is an increment of time, and abs represents an absolute function. These equations can be useful to detect unexpected fast increases or decreases in the current which could indicate that an error with the test has occurred.
Various aspects of a system for determining an analyte concentration or for determining a processing or system error are also provided herein. For example, in one embodiment the system includes an electrochemical cell having at least twoelectrodes with the cell being sized and configured to receive a sample (e.g., blood). The electrochemical cell can be further configured to determine an initial analyte concentration (e.g., glucose) and also configured to generate a pre-determinedvoltage between the first and second electrodes for a pre-determined amount of time, and further configured to measure at least one resulting current of the sample during the pre-determined time. The system can also include a processor for receiving aset of data from the electrochemical cell wherein the data can include the initial analyte concentration, a magnitude of at least one (or many) applied voltages, and at least one resulting current. The processor can further be configured to utilize thisdata to determine a corrected analyte concentration or for determining a system error (e.g., high track resistance, leakage, etc.). In one embodiment, the processor can be utilized to provide a corrected glucose concentration in view of an extremehematocrit level. In performing this function, the processor utilizes a set of equations to determine a correction term depending on the hematocrit level and the initial glucose concentration. The processor can be configured in various manners to useother equations or parameters depending on the desired calculation and/or the data obtained from the electrochemical cell.
Various aspects of a device for use in determining a corrected analyte concentration are also provided herein. In one such aspect, the device includes a test strip having a sample reaction chamber configured to receive a sample such that thesample is in communication with at least first and second electrodes. The device also includes a reagent layer disposed on at least one electrode wherein the reagent layer is formed of at least one component (e.g., a mediator, enzyme, etc.) configuredto react with the sample such that at least two voltages applied to the sample at at least two time intervals results in corresponding currents within the sample which are indicative of an initial analyte concentration and a corrected analyteconcentration.
Certain exemplary embodiments will now be described to provide an overall understanding of the principles of the structure, function, manufacture, and use of the devices, systems, and methods disclosed herein. One or more examples of theseembodiments are illustrated in the accompanying drawings. Those skilled in the art will understand that the devices and methods specifically described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments and thatthe scope of the present disclosure is defined solely by the claims. The features illustrated or described in connection with one exemplary embodiment may be combined with the features of other embodiments. Such modifications and variations areintended to be included within the scope of the present disclosure.
The presently disclosed systems and methods are suitable for use in the determination of a wide variety of analytes in a wide variety of samples, and are particularly suited for use in the determination of analytes in whole blood, plasma, serum,interstitial fluid, or derivatives thereof. In an exemplary embodiment, a glucose test system is provided which is based on a thin-layer cell design with opposing electrodes and triple pulse electrochemical detection which provides a rapid analysis time(e.g., about 5 seconds), requires a small sample (e.g., about 0.4 .mu.L), and provides improved reliability and accuracy of blood glucose measurements. In the reaction cell, glucose in the sample can be oxidized to gluconolactone using glucosedehydrogenase and an electrochemically active mediator can be used to shuttle electrons from the enzyme to a palladium working electrode. A potentiostat can be utilized to apply a triple-pulse potential waveform to the working and counter electrodes,resulting in three current transients used to calculate the glucose concentration. Further, additional information gained from the three current transients may be used to discriminate between sample matrices and correct for variability in blood samplesdue to hematocrit, temperature variation, or electrochemically active components.
The presently disclosed methods can be used, in principle, with any type of electrochemical cell having spaced apart first and second electrodes and a reagent layer. For example, an electrochemical cell can be in the form of a test strip. Inone aspect, the test strip may include two opposing electrodes separated by a thin spacer, for defining a sample-receiving chamber or zone in which a reagent layer is positioned. One skilled in the art will appreciate that other types of test strips,including, for example, test strips with co-planar electrodes as well as configurations with more than two electrodes may also be used with the methods described herein.
FIGS. 1A to 4B show various views of an exemplary test strip 62 suitable for use with the methods and systems described herein. In an exemplary embodiment, a test strip 62 is provided which includes an elongate body extending from a distal end80 to a proximal end 82, and having lateral edges 56, 58, as illustrated in FIG. 1A. As shown in FIG. 1B, the test strip 62 also includes a first electrode layer 66, a second electrode layer 64, and a spacer 60 sandwiched in between the two electrodelayers 64, 66. The first electrode layer 66 can include a first electrode 66, a first connection track 76, and a first contact pad 67, where the first connection track 76 electrically connects the first electrode 66 to the first contact pad 67, as shownin FIGS. 1B and 4B. Note that the first electrode 66 is a portion of the first electrode layer 66 that is immediately underneath the reagent layer 72, as indicated by FIGS. 1B and 4B. Similarly, the second electrode layer 64 can include a secondelectrode 64, a second connection track 78, and a second contact pad 63, where the second connection track 78 electrically connects the second electrode 64 with the second contact pad 63, as shown in FIGS. 1B, 2, and 4B. Note that the second electrode64 is a portion of the second electrode layer 64 that is above the reagent layer 72, as indicated by FIG. 4B.
As shown, a sample-receiving chamber 61 is defined by the first electrode 66, the second electrode 64, and the spacer 60 near the distal end 80 of the test strip 62, as shown in FIG. 1B and FIG. 4B. The first electrode 66 and the secondelectrode 64 can define the bottom and the top of the sample-receiving chamber 61, respectively, as illustrated in FIG. 4B. A cutout area 68 of the spacer 60 can define the sidewalls of the sample-receiving chamber 61, as illustrated in FIG. 4B. In oneaspect, the sample-receiving chamber 61 can include ports 70 that provide a sample inlet and/or a vent, as shown in FIGS. 1A-1C. For example, one of the ports can allow a fluid sample to ingress and the other port can act as a vent.
In an exemplary embodiment, the sample-receiving chamber 61 can have a small volume. For example, the chamber 61 can have a volume in the range of from about 0.1 microliters to about 5 microliters, about 0.2 microliters to about 3 microliters,or, preferably, about 0.3 microliters to about 1 microliter. To provide the small sample volume, the cutout 68 can have an area ranging from about 0.01 cm.sup.2 to about 0.2 cm.sup.2, about 0.02 cm.sup.2 to about 0.15 cm.sup.2, or, preferably, about0.03 cm.sup.2 to about 0.08 cm.sup.2. In addition, the first electrode 66 and the second electrode 64 can be spaced apart in the range of about 1 micron to about 500 microns, preferably between about 10 microns and about 400 microns, and more preferablybetween about 40 microns and about 200 microns. The relatively close spacing of the electrodes can also allow redox cycling to occur, where oxidized mediator generated at the first electrode 66, can diffuse to the second electrode 64 to become reduced,and subsequently diffuse back to the first electrode 66 to become oxidized again. Those skilled in the art will appreciate that various such volumes, areas, and/or spacing of electrodes are within the spirit and scope of the present disclosure.
In one embodiment, the first electrode layer 66 and the second electrode layer 64 can be conductive materials formed from materials such as gold, palladium, carbon, silver, platinum, tin oxide, iridium, indium, or combinations thereof (e.g.,indium doped tin oxide). In addition, the electrodes can be formed by disposing a conductive material onto an insulating sheet (not shown) by a sputtering, electroless plating, or a screen-printing process. In one exemplary embodiment, the firstelectrode layer 66 and the second electrode layer 64 can be made from sputtered palladium and sputtered gold, respectively. Suitable materials that can be employed as a spacer 60 include a variety of insulating materials, such as, for example, plastics(e.g., PET, PETG, polyimide, polycarbonate, polystyrene), silicon, ceramics, glass, adhesives, and combinations thereof. In one embodiment, the spacer 60 may be in the form of a double sided adhesive coated on opposing sides of a polyester sheet wherethe adhesive may be pressure sensitive or heat activated. Those skilled in the art will appreciate that various other materials for the first electrode layer 66, the second electrode layer 64, and/or the spacer 60 are within the spirit and scope of thepresent disclosure.
Various mechanisms and/or processes can be utilized to dispose a reagent layer 72 within the sample-receiving chamber 61. For example, the reagent layer 72 can be disposed within the sample-receiving chamber 61 using processes such as slotcoating, dispensing from the end of a tube, ink jetting, and screen printing. In one embodiment, the reagent layer 72 can include at least a mediator and an enzyme and is deposited onto the first electrode 66. Examples of suitable mediators includeferricyanide, ferrocene, ferrocene derivatives, osmium bipyridyl complexes, and quinone derivatives. Examples of suitable enzymes include glucose oxidase, glucose dehydrogenase (GDH) using a pyrroloquinoline quinone (PQQ) co-factor, GDH using anicotinamide adenine dinucleotide (NAD) co-factor, and GDH using a flavin adenine dinucleotide (FAD) co-factor [E.C.1.1.99.10]. The reagent layer 72 can be prepared from a formulation that contains 33 mM potassium citraconate, pH 6.8, 0.033% PluronicP103, 0.017% Pluronic F87, 0.85 mM CaCl.sub.2, 30 mM sucrose, 286 .mu.M PQQ, 15 mg/mL GDH, and 0.6 M ferricyanide. Pluronics are block copolymers based on ethylene oxide and propylene oxide, which can function as antifoaming agents and/or wettingagents.
The formulation can be applied at some desired rate (e.g., about 570 .mu.L/min) using a 13 gauge needle poised about 150 .mu.m above a palladium web moving at about 10 m/min. Before coating the palladium web with the enzyme formulation, the webcan be coated with 2-mercaptoethane sulfonic acid (MESA). A spacer having a desired thickness (e.g., about 95 .mu.m) with a channel cut therein having some desired width (e.g., a width of about 1.2 mm) can be laminated to the reagent layer and thepalladium web at some desired temperature (e.g., about 70.degree. C.). A MESA-coated gold web can be laminated to the other side of the spacer. The spacer can be made from a polymer substrate such as polyester coated on both sides with a thermoplasticadhesive such as Vitel, which is a linear saturated copolyester resin having a relatively high molecular weight. Release liners can optionally be laminated on top of the adhesive layer on each side of the spacer to protect the adhesive until lamination. The resulting laminate can be cut such that the fill path of the sample-receiving chamber is about 3.5 mm long, thus giving a total volume of about 0.4 .mu.L.
In one embodiment, the reagent layer 72 may have an area larger than the area of the first electrode 66. A portion of the spacer 60 may overlap and touch the reagent layer 72. The spacer 60 may be configured to form a liquid impermeable sealto the first electrode 66 even though a portion of the reagent layer 72 is between the spacer 60 and the first electrode 66. The spacer 60 may intermingle or partially dissolve a portion of the reagent layer 72 to form a liquid impermeable bond to thefirst electrode 66 sufficient to define the electrode area for at least the total test time. Under certain circumstances where the reagent layer 72 is not sufficiently dry or there is contamination such as dust particles present, the spacer 60 may notbe able to form a liquid impermeable seal and, as a result, the liquid may seep between the spacer 60 and the first electrode 66. Such a leakage event may cause an inaccurate glucose measurement to occur.
Either the first electrode 66 or the second electrode 64 can perform the function of a working electrode depending on the magnitude and/or polarity of the applied test voltage. The working electrode may measure a limiting test current that isproportional to the reduced mediator concentration. For example, if the current limiting species is a reduced mediator (e.g., ferrocyanide), then it can be oxidized at the first electrode 66 as long as the test voltage is sufficiently more positive thanthe redox mediator potential with respect to the second electrode 64. In such a situation, the first electrode 66 performs the function of the working electrode and the second electrode 64 performs the function of a counter/reference electrode. Oneskilled in the art may refer to a counter/reference electrode simply as a reference electrode or a counter electrode. A limiting oxidation occurs when all reduced mediator has been depleted at the working electrode surface such that the measuredoxidation current is proportional to the flux of reduced mediator diffusing to the working electrode surface. It should be noted that unless otherwise stated for test strip 62, all potentials applied by the test meter 100 will hereinafter be stated withrespect to the second electrode 64.
Similarly, if the test voltage is sufficiently more negative than the redox mediator potential, then the reduced mediator can be oxidized at the second electrode 64 as a limiting current. In such a situation, the second electrode 64 performsthe function of the working electrode and the first electrode 66 performs the function of the counter/reference electrode.
Initially, performing an analysis can include introducing a quantity of a fluid sample into a sample-receiving chamber 61 via a port 70. In one aspect, the port 70 and/or the sample-receiving chamber 61 can be configured such that capillaryaction causes the fluid sample to fill the sample-receiving chamber 61. The first electrode 66 and/or second electrode 64 may be coated with a hydrophilic reagent to promote the capillarity of the sample-receiving chamber 61. For example, thiolderivatized reagents having a hydrophilic moiety such as 2-mercaptoethane sulfonic acid may be coated onto the first electrode and/or the second electrode.
FIG. 5 provides a simplified schematic showing a test meter 100 interfacing with a first contact pad 67a, 67b and a second contact pad 63. The second contact pad 63 can be used to establish an electrical connection to the test meter through aU-shaped notch 65, as illustrated in FIG. 2. In one embodiment, the test meter 100 may include a second electrode connector 101, and first electrode connectors 102a, 102b, a test voltage unit 106, a current measurement unit 107, a processor 212, amemory unit 210, and a visual display 202, as shown in FIG. 5. The first contact pad 67 can include two prongs 67a, 67b. In one embodiment, the first electrode connectors 102a, 102b separately connect to the prongs 67a, 67b, respectively. The secondelectrode connector 101 can connect to the second contact pad 63. The test meter 100 can measure the resistance or electrical continuity between the prongs 67a, 67b to determine whether the test strip 62 is electrically connected to the test meter 100. One skilled in the art will appreciate that the test meter 100 can use a variety of sensors and circuits to determine when the test strip 62 is properly positioned with respect to the test meter 100.
In one embodiment, the test meter 100 can apply a test voltage and/or a current between the first contact pad 67 and the second contact pad 63. Once the test meter 100 recognizes that the strip 62 has been inserted, the test meter 100 turns onand initiates a fluid detection mode. In one embodiment, the fluid detection mode causes the test meter 100 to attempt to apply a voltage such that a constant current of about 0.5 microampere would flow between the first electrode 66 and the secondelectrode 64. Because the test strip 62 is initially dry, the test meter 100 measures a relatively large voltage, which can be limited by the maximum voltage that the test meter is capable of supplying. When the fluid sample bridges the gap between thefirst electrode 66 and the second electrode 64 during the dosing process, the test meter 100 will measure a decrease in applied voltage and when it is below a predetermined threshold will cause the test meter 100 to automatically initiate the glucosetest.
In one embodiment, the test meter 100 can perform a glucose test by applying a plurality of test voltages for prescribed intervals, as shown in FIG. 6. The plurality of test voltages may include a first test voltage V.sub.1 for a first timeinterval T.sub.1, a second test voltage V.sub.2 for a second time interval T.sub.2, and a third test voltage V.sub.3 for a third time interval T.sub.3. A glucose test time interval T.sub.G represents an amount of time to perform the glucose test (butnot necessarily all the calculations associated with the glucose test). The glucose test time interval T.sub.G can range from about 1 second to about 15 seconds or longer and more preferably from about 1 second to about 5 seconds. The plurality of testcurrent values measured during the first, second, and third time intervals may be performed at a frequency ranging from about 1 measurement per nanosecond to about one measurement per 100 milliseconds. While an embodiment using three test voltages in aserial manner is described, one skilled in the art will appreciate that the glucose test can include different numbers of open-circuit and test voltages. For example, as an alternative embodiment, the glucose test could include an open-circuit for afirst time interval, a second test voltage for a second time interval, and a third test voltage for a third time interval. One skilled in the art will appreciate that names "first," "second," and "third" are chosen for convenience and do not necessarilyreflect the order in which the test voltages are applied. For instance, an embodiment can have a potential waveform where the third test voltage can be applied before the application of the first and second test voltage.
Once the glucose assay has been initiated, the test meter 100 may apply a first test voltage V.sub.1 (e.g., about -20 mV as shown in FIG. 6) for a first time interval T.sub.1 (e.g., about 1 second as shown in FIG. 6). The first time intervalT.sub.1 can range from about 0.1 seconds to about 3 seconds and preferably range from about 0.2 seconds to about 2 seconds, and most preferably range from about 0.3 seconds to about 1 seconds.
The first time interval T.sub.1 may be sufficiently long so that the sample-receiving chamber 61 can fully fill with sample and also so that the reagent layer 72 can at least partially dissolve or solvate. In one aspect, the first test voltageV.sub.1 may be a relatively low value so that a relatively small amount of a reduction or oxidation current is measured. FIG. 7 shows that a relatively small amount of current is observed during the first time interval T.sub.1 compared to the second andthird time intervals T.sub.2 and T.sub.3. For example, when using ferricyanide and/or ferrocyanide as the mediator, the first test voltage V.sub.1 can range from about -100 mV to about -1 mV, preferably range from about -50 mV to about -5 mV, and mostpreferably range from about -30 mV to about -10 mV.
After applying the first test voltage V.sub.1, the test meter 100 applies a second test voltage V.sub.2 between the first electrode 66 and the second electrode 64 (e.g., about -0.3 Volts as shown in FIG. 6), for a second time interval T.sub.2(e.g., about 3 seconds as shown in FIG. 6). The second test voltage V.sub.2 may be a value sufficiently negative of the mediator redox potential so that a limiting oxidation current is measured at the second electrode 64. For example, when usingferricyanide and/or ferrocyanide as the mediator, the second test voltage V.sub.2 can range from about -600 mV to about zero mV, preferably range from about -600 mV to about -100 mV, and more preferably be about -300 mV.
The second time interval T.sub.2 should be sufficiently long so that the rate of generation of reduced mediator (e.g., ferrocyanide) can be monitored based on the magnitude of a limiting oxidation current. Reduced mediator is generated byenzymatic reactions with the reagent layer 72. During the second time interval T.sub.2, a limiting amount of reduced mediator is oxidized at the second electrode 64 and a non-limiting amount of oxidized mediator is reduced at the first electrode 66 toform a concentration gradient between the first electrode 66 and the second electrode 64.
In an exemplary embodiment, the second time interval T.sub.2 should also be sufficiently long so that a sufficient amount of ferricyanide can be generated at the second electrode 64. A sufficient amount of ferricyanide is required at the secondelectrode 64 so that a limiting current can be measured for oxidizing ferrocyanide at the first electrode 66 during the third test voltage V.sub.3. The second time interval T.sub.2 may be less than about 60 seconds, preferably range from about 1 secondto about 10 seconds, and more preferably range from about 2 seconds to about 5 seconds.
FIG. 7 shows a relatively small peak i.sub.pb at the beginning of the second time interval T.sub.2 followed by a gradual increase of an absolute value of an oxidation current during the second time interval T.sub.2. The small peak i.sub.pboccurs due to an initial depletion of reduced mediator at about 1 second. The gradual increase in oxidation current after the small peak i.sub.pb is caused by the generation of ferrocyanide by reagent layer 72, which then diffuses to second electrode64.
After applying the second test voltage V.sub.2, the test meter 100 applies a third test voltage V.sub.3 between the first electrode 66 and the second electrode 64 (e.g., about +0.3 Volts in FIG. 6) for a third time interval T.sub.3 (e.g., 1second in FIG. 6). The third test voltage V.sub.3 may be a value sufficiently positive of the mediator redox potential so that a limiting oxidation current is measured at the first electrode 66. For example, when using ferricyanide and/or ferrocyanideas the mediator, the third test voltage V.sub.3 can range from about 0 mV to about 600 mV, preferably range from about 100 mV to about 600 mV, and more preferably be about 300 mV.
The third time interval T.sub.3 may be sufficiently long to monitor the diffusion of reduced mediator (e.g., ferrocyanide) near the first electrode 66 based on the magnitude of the oxidation current. During the third time interval T.sub.3, alimiting amount of reduced mediator is oxidized at first electrode 66 and a non-limiting amount of oxidized mediator is reduced at the second electrode 64. The third time interval T.sub.3 can range from about 0.1 seconds to about 5 seconds andpreferably range from about 0.3 seconds to about 3 seconds, and more preferably range from about 0.5 seconds to about 2 seconds.
FIG. 7 shows a relatively large peak i.sub.p, at the beginning of the third time interval T.sub.3 followed by a decrease to a steady-state current i.sub.ss value. In one embodiment, the second test voltage V.sub.2 can have a first polarity andthe third test voltage V.sub.3 may have a second polarity that is opposite to the first polarity. In another embodiment, the second test voltage V.sub.2 can be sufficiently negative of the mediator redox potential and the third test voltage V.sub.3 canbe sufficiently positive of the mediator redox potential. The third test voltage V.sub.3 may be applied immediately after the second test voltage V.sub.2. However, one skilled in the art will appreciate that the magnitude and polarity of the second andthird test voltages can be chosen depending on the manner in which analyte concentration is determined.
Assuming that a test strip has an opposing face or facing arrangement as shown in FIGS. 1A-4B, and that a potential waveform is applied to the test strip as shown in FIG. 6, an initial glucose concentration G.sub.1 can be calculated using aglucose algorithm as shown in Equation 1.
In Equation 1, i.sub.1 is a first test current value, i.sub.2 is a second test current value, and i.sub.3 is a third test current value, and the terms p, z, and a are empirically derived calibration constants. All test current values (i.e.,i.sub.1, i.sub.2, and i.sub.3) in Equation 1 use the absolute value of the current. The first test current value i.sub.1 and the second test current value i.sub.2 can each be defined by an average or summation of one or more predetermined test currentvalues that occur during the third time interval T.sub.3. The third test current value i.sub.3 can be defined by an average or summation of one or more predetermined test current values that occur during the second time interval T.sub.2. One skilled inthe art will appreciate that names "first," "second," and "third" are chosen for convenience and do not necessarily reflect the order in which the current values are calculated.
Equation 1 can be modified to provide an even more accurate glucose concentration. Instead of using a simple average or summation of test current values, the term i.sub.1 can be defined to include peak current values i.sub.pb and i.sub.p, andthe steady-state current i.sub.ss, as shown in Equation 2.
A calculation of the steady-state current i.sub.ss can be based on a mathematical model, an extrapolation, an average at a predetermined time interval, or a combination thereof. One example of a method for calculating i.sub.ss can be found inU.S. Pat. No. 6,413,410 and U.S. Pat. No. 5,942,102, the entirety of these patents being incorporated herein by reference.
In addition to endogenous interferents, extreme hematocrit levels under certain circumstances can affect the accuracy of a glucose measurement. Thus, Equation 3 can be further modified to provide a corrected glucose concentration G.sub.2 thatis accurate even if the sample has an extreme hematocrit level (e.g., about 10% or about 70%).
Additionally, various embodiments of a method and system configured to account for and/or identify various system, user, and/or device inefficiencies and/or errors are provided herein. For example, in one embodiment, the system can accuratelydetermine a glucose concentration of a sample having an extreme hematocrit level. Additionally, the system can be configured to identify a test utilizing a partial fill or double-fill of a sample chamber. Also, the system can be configured to identifythose situations where the sample may be leaking from the sample chamber thereby compromising the integrity of the testing and/or those situations where some portion of system (e.g., the test strip) is damaged. These various embodiments are describedbelow.
Methods and systems of accurately measuring glucose concentrations in extreme hematocrit samples are provided herein. For example, FIG. 8 is a flow diagram depicting a method 2000 for calculating an accurate glucose concentration that accountsfor blood samples having an extreme hematocrit level. A user can initiate a test by applying a sample to the test strip, as shown in step 2001. A first test voltage V.sub.1 can be applied for a first time interval T.sub.1, as shown in step 2002. Theresulting test current is then measured for the first time interval T.sub.1, as shown in step 2004. After the first time interval T.sub.1, the second test voltage V.sub.2 is applied for a second time interval T.sub.2, as shown in step 2006. Theresulting test current is then measured for the second time interval T.sub.2, as shown in step 2008. After the second time interval T.sub.2, the third test voltage V.sub.3 is applied for a third time interval T.sub.3, as shown in step 2010. Theresulting test current is then measured for the third time interval T.sub.3, as shown in step 2012.
Now that test current values have been collected by a test meter, an initial glucose concentration G.sub.1 can be calculated, as shown in step 2014. The initial glucose concentration G.sub.1 can be calculated using Equation 1 or Equation 3. Next, a hematocrit level H can be calculated, as shown in step 2016.
The hematocrit level may be estimated using test current values acquired during the glucose test time interval T.sub.G. Alternatively, the hematocrit level H may be estimated using test current values acquired during the second time intervalT.sub.2 and the third time interval T.sub.3. In one embodiment, the hematocrit level H can be estimated using a hematocrit equation based upon the initial glucose concentration G.sub.1 and the second test current value i.sub.2. An exemplary hematocritequation is shown in Equation 4. H=K.sub.5 ln(|i.sub.2|)+K.sub.6 ln(G.sub.1)+K.sub.7 Eq. 4
The term H is the hematocrit level, i.sub.2 is at least one current value during the second time interval, K.sub.5 is a fifth constant, K.sub.6 is a sixth constant, and K.sub.7 is a seventh constant. In one embodiment, K.sub.5, K.sub.6, andK.sub.7 may be -76, 56, and, 250, respectively. FIG. 9 shows that the estimated hematocrit levels using Equation 4 has an approximately linear correlation with actual hematocrit levels measured with a reference method.
Once the hematocrit level H has been calculated in step 2016, it is compared to a lower predetermined hematocrit level H.sub.L, as shown in step 2018. The lower predetermined hematocrit level H.sub.L may be about 30%. If the hematocrit level His less than the lower predetermined hematocrit level H.sub.L, then the initial glucose concentration G.sub.1 is compared to an upper predetermined glucose concentration G.sub.U, as shown in step 2020. The upper predetermined glucose concentrationG.sub.U may be about 300 mg/dL. If the hematocrit level H is not less than the lower predetermined hematocrit level H.sub.L, then the hematocrit level H is compared to an upper predetermined hematocrit level H.sub.U, as shown in step 2022. The upperpredetermined hematocrit level H.sub.U may be about 50%. If the hematocrit level H is greater than H.sub.U, then the initial glucose concentration G.sub.1 is compared to a lower predetermined glucose concentration G.sub.L, as shown in step 2028. Thelower predetermined glucose concentration G.sub.L may be about 100 mg/dL. Steps 2018 and 2022 indicate that method 2000 will output the initial glucose concentration G.sub.1, as shown in step 2034, if the hematocrit level H is not less than H.sub.L andnot greater than H.sub.U.
A first function can be used to calculate a correction value Corr, as shown in step 2024, if H is less than H.sub.L and if the initial glucose concentration G.sub.1 is less than the upper predetermined glucose concentration G.sub.U. The firstfunction may be in the form of Equation 5. Corr=K.sub.1(H.sub.L-H)G.sub.1 Eq. 5
The term K.sub.1 is a first constant and H.sub.L is the lower predetermined hematocrit level. In one embodiment, K.sub.1 and H.sub.L may be -0.004 and about 30%, respectively.
However, if H is less than H.sub.L and if the initial glucose concentration G.sub.1 is not less than the upper predetermined glucose concentration G.sub.U, then the second function can be used to calculate the correction value Corr, as shown instep 2026. The second function may be in the form of Equation 6. Corr=K.sub.2(H.sub.L-H)(G.sub.max-G.sub.1) Eq. 6
The term K.sub.2 is a second constant and G.sub.max is a predetermined maximum glucose concentration. In one embodiment, K.sub.2 and G.sub.max may be -0.004 and about 600 mg/dL, respectively. The correction value Corr for Equations 5 and 6 maybe restricted to a range of about -5 to about zero. Thus, if Corr is less than -5, then Corr is set to -5 and if Corr is greater than zero then Corr is set to zero.
A third function can be used to calculate a correction value Corr, as shown in step 2030, if H is greater than H.sub.U and if the initial glucose concentration G.sub.1 is less than a lower predetermined glucose concentration G.sub.L. The thirdfunction may be in the form of Equation 7. Corr=0 Eq. 7
However, if H is greater than H.sub.U and if the initial glucose concentration G.sub.1 is not less than the lower predetermined glucose concentration G.sub.L, then the fourth function can be used to calculate the correction value Corr, as shownin a step 2032. The fourth function may be in the form of Equation 8. Corr=K.sub.4(H-H.sub.U)(G.sub.1-G.sub.L) Eq. 8
The term K.sub.4 is a fourth constant, which may be about 0.011. The correction value Corr for Equation 8 may be restricted to a range of about zero to about six. Thus, if Corr is less than zero, then Corr is set to zero and if Corr is greaterthan six then Corr is set to six.
After calculating Corr with the first function in step 2024, the first glucose concentration is compared to 100 mg/dL in step 2036. If the first glucose concentration is less than 100 mg/dL, then the second glucose concentration G.sub.2 iscalculated using a first correction equation, as shown in step 2038. Note that the 100 mg/dL represents a glucose threshold and should not be construed as a limiting number. In one embodiment, the glucose threshold may range from about 70 mg/dL toabout 100 mg/dL. The first correction equation may be in the form of Equation 9. G.sub.2=G.sub.1+Corr. Eq. 9
If the initial glucose concentration G.sub.1 is not less than 100 mg/dL based on step 2036, then the corrected glucose concentration G.sub.2 is calculated using a second correction equation, as shown in step 2040. The second correction equationmay be in the form of Equation 10.
After the corrected glucose concentration G.sub.2 is calculated in either step 2038 or step 2040, it is outputted as a glucose reading in step 2042.
After calculating Corr in step 2026, step 2030, or step 2032, the corrected glucose concentration G.sub.2 can be calculated using Equation 10, as shown in step 2040. When Corr equals zero (as for the third function), the corrected glucoseconcentration G.sub.2 equals the initial glucose concentration G.sub.1, which can then be outputted as a glucose reading in step 2042.
The method 2000 for calculating accurate glucose concentrations in blood samples having extreme hematocrit levels was verified using blood from several donors. FIG. 10 shows a bias plot for a plurality of test strips that were tested with bloodsamples having a wide range of hematocrit levels and glucose concentrations. More specifically, FIG. 10 shows the effect of whole blood samples having a wide range of hematocrit on the accuracy and precision of the new test system. As shown, the biasof the sensor response with respect to the YSI 2700 instrument (Yellow Springs Instruments, Yellow Springs, Ohio) is plotted against the plasma glucose concentration. The data were obtained with 3 batches of sensors and 4 blood donors. The hematocritwas adjusted to 20% (squares), 37-45% (circles) or 60% (triangles) prior to spiking the samples with glucose. These data suggest that the thin layer cell and triple-pulse approach for electrochemical measurement offers the opportunity for improvedanalytical performance with blood glucose test systems. Thus, the use of the correction value Corr, which depends on the hematocrit level H and the initial glucose concentration G.sub.1, allows for the determination of a more accurate corrected glucoseconcentration G.sub.2 even if the blood sample has an extreme hematocrit level.
Various embodiments of a method for identifying system errors, which may include user errors when performing a test, test meter errors, and defective test strips, are also provided. For example, FIG. 11 is a flow diagram depicting an exemplaryembodiment of a method 1000 of identifying system errors in performing an analyte measurement. As shown, a user can initiate a test by applying a sample to a test strip, as shown in step 1002. After the sample has been dosed, the test meter applies afirst test voltage V.sub.1 for a first time interval T.sub.1, as shown in step 1004a. A resulting test current is then measured for the first time interval T.sub.1, as shown in step 1005a. During the first time interval T.sub.1, the test meter performsa double dose check 1006a, and a maximum current check 1012a. If either the double dose check 1006a or maximum current check 1012a fails, then the test meter will display an error message, as shown in step 1028. If the double dose check 1006a andmaximum current check 1012a both pass, then the test meter can apply a second test voltage V.sub.2 for a second time interval T.sub.2, as shown in step 1004b.
A resulting test current is measured for the second time interval T.sub.2, as shown in step 1005b. During the application of the second test voltage V.sub.2, the test meter performs a double dose check 1006b, a maximum current check 1012b, anda minimum current check 1014b. If one of the checks 1006b, 1012b, or 1014b fail, then the test meter will display an error message, as shown in step 1028. If all of the checks 1006b, 1012b, and 1014b pass, then the test meter will apply a third testvoltage V.sub.3, as shown in step 1004c.
A resulting test current is measured for the third time interval T.sub.3, as shown in step 1005c. During the application of the third test voltage V.sub.3, the test meter performs a double dose check 1006c, maximum current check 1012c, aminimum current check 1014c, a high resistance check 1022c, and a sample leakage check 1024c. If all of the checks 1006c, 1012c, 1014c, 1022c, and 1024c pass, then the test meter will display a glucose concentration, as shown in step 1026. If one ofthe checks 1006c, 1012c, 1014c, 1022c, and 1024c fails, then the test meter will display an error message, as shown in step 1028.
A double dose occurs when a user applies an insufficient volume of blood to a sample-receiving chamber and then applies a subsequent bolus of blood to further fill the sample-receiving chamber. An insufficient volume of blood expressed on auser's fingertip or a shaky finger can cause the occurrence of a double-dosing event. The currently disclosed system and method can be configured to identify such double-fill events. For example, FIG. 12 shows a test current transient where adouble-dosing event occurs during the second test time interval T.sub.2 thereby causing a spike to be observed (see solid line). When there is no double-dosing event, the test current transient does not have a peak (see dotted line of FIG. 12).
A double-dosing event can cause a glucose test to have an inaccurate reading. Thus, it is usually desirable to identify a double-dosing event and then have the meter output an error message instead of outputting a potentially inaccuratereading. A double-dosing event initially causes the measured test current to be low in magnitude because the electrode area is effectively decreased when only a portion is wetted with sample. Once the user applies the second dose, a current spike willoccur because of a sudden increase in the effective electrode area and also because turbulence causes more reduced mediator to be transported close to the working electrode. In addition, less ferrocyanide will be generated because a portion of thereagent layer is not wetted by the sample for the entire test time. Thus, an inaccurate glucose reading can result if a test current value used in the glucose algorithm is depressed or elevated as a result of the double-dosing.
A method of identifying a double-dosing event (1006a, 1006b, or 1006c) may include measuring a second test current and a third test current where the second test current occurs before the third test current. An equation may be used to identifydouble-dosing events based on a difference between the absolute value of the third test current and the absolute value of the second test current. If the difference is greater than a predetermined threshold, the test meter can output an error messageindicative of a double-dosing event. The method of identifying the double-dosing event may be performed multiple times in serial manner as the test current values are collected by the test meter. The equation can be in the form of Equation 11 forcalculating a difference value Z for determining whether a double-dosing event had occurred. Z=abs(i(t+x))-abs(i(t)) Eq. 11
The terms i(t) is a second test current, i(t+x) is a third test current, t is a time for the second test current, and x is an increment of time in between current measurements. If the value Z is greater than a predetermined threshold of about 3microamperes, then the test meter may output an error message due to a double-dosing event. The predetermined thresholds disclosed herein are illustrative for use with test strip 100 and with the test voltage waveform of FIG. 6 where the workingelectrode and the reference electrode both have an area of about 0.042 cm.sup.2 and a distance between the two electrodes ranging from about 90 microns to about 100 microns. It should be obvious to one skilled in the art that such predeterminedthresholds may change based on the test strip design, the test voltage waveform, and other factors.
In another embodiment for identifying a double-dosing event (e.g., 1006a, 1006b, or 1006c), a method is provided which includes measuring a first test current, a second test current, and a third test current where the first test current occursbefore the second test current and the third test current occurs after the second test current. An equation is provided to identify double-dosing events based on two times the absolute value of the second test current minus the absolute value of firsttest current and minus the absolute value of the third test current. The equation may be in the form of Equation 12 for calculating a summation value Y for determining whether a double-dosing event had occurred. Y=2*abs(i(t))-abs(i(t-x))-abs(i(t+x))Eq. 12
The terms i(t) is a second test current, i(t-x) is a first test current, i(t+x) is a third test current, t is a time for the second test current, and x is an increment of time in between measurements, and abs represents an absolute function. Ifthe summation value Y is greater than a predetermined threshold, then the test meter may output an error message due to a double-dosing event. The predetermined threshold may be set to a different value for the first time interval T.sub.1, the secondtime interval T.sub.2, and the third time interval T.sub.3.
In one embodiment, the predetermined threshold may be about 2 microamperes for the first time interval T.sub.1, about 2 microamperes for the second time interval T.sub.2, and about 3 microamperes for the third time interval T.sub.3. Thepredetermined thresholds may be adjusted as a result of the various factors such as, for example, noise in the test meter, frequency of test current measurements, the area of the electrodes, the distance between the electrodes, the probability of a falsepositive identification of a double-dosing event, and the probability of a false negative identification of a double-dosing event. The method of identifying the double-dosing event using Equation 12 can be performed for multiple portions of the testcurrent transient. It should be noted that Equation 12 can be more accurate than Equation 11 for identifying double-dosing events because the first test current and third test current provide a baseline correction. When using the test voltage waveformof FIG. 7, the double-dosing check can be performed at a time period just after the beginning of the first, second, and third time intervals because a peak typically occurs at the beginning of the time intervals. For example, the test currents measuredat zero seconds to about 0.3 seconds, about 1.05 seconds, and about 4.05 seconds should be excluded from the double-dosing check.
As referred to in steps 1012a, 1012b, and 1012c of FIG. 11, a maximum current check can be used to identify a test meter error or a test strip defect. An example of a test meter error occurs when the blood is detected late after it is dosed. An example of a defective test strip occurs when the first and second electrodes are shorted together. FIG. 13 shows a test current transient where the test meter did not immediately detect the dosing of blood into the test strip (see solid line). Insuch a scenario, a late start will generate a significant amount of ferrocyanide before the second test voltage V.sub.2 is applied causing a relatively large test current value to be observed. In contrast, when the test meter properly initiates the testvoltage waveform once blood is applied, the test current values for the second time interval are much smaller, as illustrated by the dotted line in FIG. 13.
A late start event can cause an inaccurate glucose reading. Thus, it would be desirable to identify a late start event and then have the meter output an error message instead of outputting an inaccurate reading. A late start event causes themeasured test current to be larger in magnitude because there is more time for the reagent layer to generate ferrocyanide. Thus, the increased test current values will likely distort the accuracy of the glucose concentration.
Maximum current check (1012a, 1012b, and 1012c) can be performed by comparing the absolute value of all of the measured test current values to a predetermined threshold and outputting an error message if the absolute value of one of the measuredtest current values is greater than the predetermined threshold. The predetermined threshold can be set to a different value for the first, second, and third test time intervals (T.sub.1, T.sub.2, and T.sub.3). In one embodiment, the predeterminedthreshold may be about 50 microamperes for the first time interval T.sub.1, about 300 microamperes for the second time interval T.sub.2, and about 3000 microamperes for the third time interval T.sub.3.
As referred to in steps 1014b and 1014c of FIG. 11, a minimum current check can be used to identify various potential issues, such as, for example, a false start of a glucose test, an improper time shift by a test meter, and a premature teststrip removal. A false start can occur when the test meter initiates a glucose test even though no sample has been applied to the test strip. Examples of situations that can cause a test meter to inadvertently initiate a test are an electrostaticdischarge event (ESD) or a temporary short between first and second electrodes. Such events can cause a relatively large current to be observed for a least a short moment in time that initiates a test even though no liquid sample has been introducedinto the test strip.
An inadvertent initiation of a glucose test can cause a test meter to output a low glucose concentration even though no sample has yet been applied to the test strip. Thus, it would be desirable to identify an inadvertent initiation of aglucose test so that the test meter does not output a falsely low glucose reading. Instead, the test meter should provide an error message that instructs the user to re-insert the same test strip or to insert a new test strip for performing the testagain.
A time shifting error by the test meter can occur when the third test voltage V.sub.3 is applied early or late. An early application of the third test voltage V.sub.3 should cause the test current value at the end of the second time intervalT.sub.2 to be a relatively large current value with a positive polarity instead of a relatively small current value with a negative polarity. A late application of the third test voltage V.sub.3 should cause the test current value at the beginning ofthe third time interval to be a relatively small current value with a negative polarity instead of a relatively large current value with a positive polarity. For both the early and late application of the third test voltage V.sub.3, there is apossibility of causing an inaccurate glucose result. Therefore, it would be desirable to identify a time shifting error by the test meter using the minimum current check so that an inaccurate glucose reading does not occur.
A premature removal of a test strip from the test meter before the end of a glucose test can also cause an inaccurate glucose reading to occur. A test strip removal would cause the test current to change to a value close to zero potentiallycausing an inaccurate glucose output. Accordingly, it would also be desirable to identify a premature strip removal using a minimum current check so that an error message can be provided instead of displaying an inaccurate glucose reading.
The minimum current check may be performed by comparing the absolute value of all of the measured test current values during the second and third time intervals (T.sub.2 and T.sub.3) to a predetermined threshold and outputting an error messageif the absolute value of one of the measured test current values is less than a predetermined threshold. The predetermined threshold may be set to a different value for the second and third test time intervals. However, in one embodiment, thepredetermined threshold may be about 1 microampere for the first time interval T.sub.1 and the second time interval T.sub.2. Note that the minimum current check was not performed for the first time interval because the test current values are relativelysmall because the first test voltage is close in magnitude to the redox potential of the mediator.
As referred to in step 1022c of FIG. 11, a high resistance track can be detected on a test strip that can result in an inaccurate glucose reading. A high resistance track can occur on a test strip that has an insulating scratch or a fouledelectrode surface. For the situation in which the electrode layers are made from a sputtered gold film or sputtered palladium film, scratches can easily occur during the handling and manufacture of the test strip. For example, a scratch that runs fromone lateral edge 56 to another lateral edge 58 on first electrode layer 66 can cause an increased resistance between the first contact pads 67 and the first electrode 66. Sputtered metal films tend to be very thin (e.g., about 10 nm to about 50 nm)making them prone to scratches during the handling and manufacture of the test strip. In addition, sputtered metal films can be fouled by exposure to volatile compounds such as, for example, hydrocarbons. This exposure causes an insulating film to formon the surface of the electrode, which increases the resistance. Another scenario that can cause a high resistance track is when the sputtered metal film is too thin (e.g., less than about 10 nm). Yet another scenario that can cause a high resistancetrack is when the test meter connectors do not form a sufficiently conductive contact to the test strip contact pads. For example, the presence of dried blood on the test meter connectors can prevent sufficiently conductive contact to the test stripcontact pads.
FIG. 14 shows two test current transients during a third time interval T.sub.3 for a test strip having a high resistance track (squares) and a low resistance track (triangles). A sufficiently high resistance R that is between the electrode andthe electrode contact pad can substantially attenuate the magnitude of the effectively applied test voltage V.sub.eff, which in turn can attenuate the magnitude of the resulting test current. The effective test voltage V.sub.eff can be described byEquation 13. V.sub.eff=V-i(t)R Eq. 13
V.sub.eff will be the most attenuated at the beginning of the third time interval T.sub.3 where the test current will generally have the highest magnitude. The combination of a relatively large track resistance R and a relatively large testcurrent at the beginning of the third time interval T.sub.3 can cause a significant attenuation in the applied test voltage. In turn, this could cause an attenuation of the resulting test current at the beginning of the third time interval T.sub.3, asillustrated in FIG. 14 at t=4.05 seconds. Such attenuation in the peak current immediately at about 4.05 seconds can cause the calculated glucose concentration to be inaccurate. In order to avoid significant attenuation in the applied test voltage, thetrack resistance R should be a relatively small value (i.e., low track resistance). In one embodiment, a low resistance track may be represented by an electrode layer having a resistivity of less than about 12 ohms per square and a high resistance trackmay be represented by an electrode layer having a resistivity of greater than about 40 ohms per square.
A determination of whether a test strip has a high track resistance can use an equation based on a first test current i.sub.1 and a second test current i.sub.2 that both occur during the third time interval T.sub.3. The first test currenti.sub.1 may be measured at about a beginning of the third time interval T.sub.3 (e.g., about 4.05 seconds) where the magnitude is at a maximum or close to the maximum. The second test current i.sub.2 may be measured at about an end of the third timeinterval T.sub.3 (e.g., about 5 seconds) where the magnitude is at the minimum or close to the minimum.
If the first ratio R.sub.1 is greater than a predetermined threshold, then the test meter may output an error message due to the test strip having a high resistance track. The predetermined threshold may be about 1.2. It is significant thatthe first test current i.sub.1 is about a maximum current value because it is the most sensitive to resistance variations according to Eq. 13. If a first test current i.sub.1 is measured at a time that was closer to the minimum current value, thenEquation 14 would be less sensitive for determining whether a high resistance track was present. It is advantageous to have relatively low variation in the first ratio R.sub.1 when testing low resistance test strips. The relatively low variationdecreases the likelihood of mistakenly identifying a high resistance track test strip. As determined and described herein, the variation of first ratio R.sub.1 values for test strips having a low resistance track is about four times lower when a firsttest current value i.sub.1 was defined as a current value immediately after the application of the third test voltage V.sub.3, as opposed to being a sum of current values during the third time interval T.sub.3. When there is a high variation in firstratio R.sub.1 values for low resistance test strips, the probability of mistakenly identifying a high resistance track increases.
FIG. 15 is a chart showing a plurality of R.sub.1 values calculated with Equation 14 for two test strip lots where one lot has a high resistance track and the other lot has a low resistance track. One lot of test strip was purposelymanufactured with a high resistance track by using palladium electrodes that were purposely fouled by an exposure to an atmosphere containing hydrocarbons for several weeks. The second test strip lot was manufactured without purposely fouling theelectrode surface. To prevent fouling, a roll of sputtered coated palladium was coated with MESA before coating with the reagent layer. All of the low resistance test strips, which were not fouled, had R.sub.1 values of less than about 1.1 indicatingthat Equation 14 could identify low track resistance test strips. Similarly, essentially all of the high resistance test strips, which were purposely fouled, had R.sub.1 values of greater than about 1.1 indicating that Equation 14 could identify hightrack resistance test strips.
As previously referred to in step 1024c in FIG. 11, a leakage can be detected on a test strip when the spacer 60 does not form a sufficiently strong liquid impermeable seal with the first electrode layer 66. A leakage occurs when liquid seepsin between the spacer 60 and the first electrode 66 and/or the second electrode 64. FIG. 4B shows a reagent layer 72 that is immediately adjacent to the walls of the spacer 60. However, in another embodiment (not shown) where leakage is more likely tooccur, the reagent layer 72 can have an area larger than the cutout area 68 that causes a portion of the reagent layer 72 to be in between the spacer 60 and the first electrode layer 66. Under certain circumstances, interposing a portion of the reagentlayer 72 in between the spacer 60 and the first electrode layer 66 can prevent the formation of a liquid impermeable seal. As a result, a leakage can occur which creates an effectively larger area on either the first electrode 66, which in turn, cancause an inaccurate glucose reading. An asymmetry in the area between the first electrode 66 and the second electrode 64 can distort the test current transient where an extra hump appears during the third time interval T.sub.3, as illustrated in FIG.16.
FIG. 16 shows test current transients during a third time interval T.sub.3 for three different types of test strip lots where test strip lot 1 (squares) has a leakage of liquid between the spacer and the first electrode. Test strip lot 1 wasconstructed using a dryer setting that did not sufficiently dry the reagent layer and also was laminated with a pressure setting that was not sufficient to form a liquid impermeable seal to the electrodes. Normally, the reagent layer is sufficientlydried so that an adhesive portion of the spacer 60 can intermingle with the reagent layer and still forms a liquid impermeable seal to the first electrode layer 66. In addition, sufficient pressure must be applied so that the adhesive portion of thespacer 60 can form the liquid impermeable seal to the first electrode layer 66. The test strip lot 2 was prepared similarly to test strip lot 1 except that they were stored at about 37.degree. Celsius for about two weeks. The storage of the test striplot 2 caused the adhesive bond to anneal creating a liquid impermeable seal to the electrodes. Test strip lot 3 was constructed using a dryer setting that was sufficient to dry the reagent layer and also was laminated with a pressure setting sufficientto form a liquid impermeable seal. Both test strip lots 2 and 3 (triangles and circles respectively) show a more rapid decay in the test current magnitude with time compared to test strip 1 (squares), as illustrated in FIG. 16.
A determination of whether a test strip leaks can be performed using an equation based on a first test current, a second test current, a third test current, and a fourth test current that occur during the third test time interval. A firstlogarithm of a second ratio can be calculated based on a first test current i.sub.1 and a second test current i.sub.2. A second logarithm of a third ratio can be calculated based on a third test current i.sub.3 and a fourth test current i.sub.4. Anequation may be used to calculate a fourth ratio R.sub.4 based on the first logarithm and the second logarithm. If the fourth ratio R.sub.4 is less than a predetermined ratio, then the test meter will output an error message due to leakage. Thepredetermined threshold may range from about 0.95 to about 1. The equation for identifying leakage can be in the form of Equation 15.
.function..function..times. ##EQU00010##
In one embodiment, the first test current i.sub.1 and the second test i.sub.2 current may be about the two largest current values occurring during the third time interval T.sub.3. The fourth test current i.sub.4 may be a smallest current valueoccurring during the third time interval T.sub.3. The third test current i.sub.3 may be selected at a third test time so that a difference between the fourth test time and a third test time is greater than a difference between a second test time and afirst test time. In one illustrative embodiment, the first test current, the second test current, the third test current, and the fourth test current may be measured at about 4.1 seconds, about 4.2 seconds, about 4.5 seconds, and about 5 seconds,respectively.
FIG. 17 is a chart showing a plurality of R.sub.4 values calculated with Equation 15 for the three test strip lots described for FIG. 16. Accordingly, test strip lot 1 has fourth ratio values less than one and both test strip lots 2 and 3 havefourth ratio R.sub.4 values greater than one indicating that Equation 15 can successfully identify strip leakages.
In an alternative embodiment, a determination of whether a test strip has a leakage can be performed using an equation based on three test current values instead of using four test current values as shown in Equation 15. The three test currentvalues may include a first test current i.sub.1, a third test current i.sub.3, and a fourth test current i.sub.4 that all occur during the third test time interval T.sub.3. A third logarithm of a fifth ratio may be calculated based on the first testcurrent i.sub.1 and the third test current i.sub.3. A second logarithm of a third ratio may be calculated based on the third test current i.sub.3 and the fourth test current i.sub.4. An equation may be used to calculate a sixth ratio R.sub.6 based onthe third logarithm and the second logarithm. If R.sub.6 is less than a predetermined ratio, then the test meter will output an error message due to leakage. The equation for identifying leakage may be in the form of Equation 16.
One skilled in the art will appreciate further features and advantages of the present disclosure based on the above-described embodiments. Accordingly, the present disclosure is not to be limited by what has been particularly shown anddescribed, except as indicated by the appended claims. All publications and references cited herein are expressly incorporated herein by reference in their entirety.
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