HK1132643B - Abnormal output detection system for a biosensor - Google Patents

Description

Abnormal output detection system for biosensor

Reference to related applications

Priority of U.S. provisional application No.60/746,771 entitled "Abnormal Output detection System for a Biosensor", filed 2006, 8/5, is hereby incorporated by reference in its entirety.

Background

Biosensors typically provide for the analysis of biological fluids such as whole blood, urine or saliva. In general, biosensors analyze a sample of a biological fluid to determine the concentration of one or more analytes, such as glucose, uric acid, lactate, cholesterol, or bilirubin, in the biological fluid. Such analysis can be used to diagnose and treat physiological abnormalities. For example, a diabetic may use a biosensor to determine the glucose level in the blood to adjust diet and/or medication.

The biosensor may provide an abnormal output during analysis of the biological fluid. The abnormal output may be in response to an error during the analysis of the biological fluid. Errors may arise from one or more factors such as the physical characteristics of the sample, environmental aspects of the sample, operating conditions of the biosensor, interfering substances, and the like. Physical characteristics of the sample include hematocrit level, etc. Environmental aspects of the sample include temperature, etc. Operating conditions of the biosensor include underfill conditions when the sample size is not large enough, slow filling of the sample, intermittent electrical contact between the sample and one or more electrodes in the biosensor, and the like. Interfering substances include ascorbic acid, acetaminophen, and the like. There may be other factors and/or combinations of factors that may cause errors and/or abnormal output.

Biosensor available bench topDevices, portable devices, and the like. The portable device may be hand-held. Biosensors may be designed to analyze one or more analytes, and may use different amounts of biological fluids. Some biosensors may analyze a drop of whole blood, for example, a volume of 0.25-15 microliters (μ L) of whole blood. Examples of portable measuring devices include: ascensia available from Bayer CorporationAnda measuring instrument; available from Abbott, Abbott Park, IllinoisA biosensor; available from Roche of Indianapolis, IndianaA biosensor; and OneTouch available from Lifescan of Milpitas, CaliforniaA biosensor. Examples of bench-top measuring devices include: BAS100B Analyzer available from BAS Instruments of West Lafayette, Indiana; CH Instruments electrochemical workbench available from CH Instruments of Austin, Texas; cypress electrochemical workbench available from Cypress Systems of Lawrence, Kansas; and EG available from Princeton research instruments of Princeton City, N.J.&G electrochemical instrument.

Biosensors typically measure an electrical signal to determine the analyte concentration in a sample of a biological fluid. When an input signal is applied to the sample, the analyte typically undergoes an oxidation/reduction reaction or a redox reaction. An enzyme or the like may be added to the sample to enhance the redox reaction. The input signal is typically an electrical signal, such as a current or a potential. The redox reaction generates an output signal in response to an input signal. The output signal is typically an electrical signal, such as a current or potential, which can be measured and correlated to the analyte concentration in the biological fluid.

Many biosensors have a measuring device and a sensor strip. A sample of biological fluid is introduced into the sample chamber in the sensor strip. The sensor strip is placed in a measuring device for analysis. The measuring device typically has electrical contacts that connect with electrical conductors in the sensor strip. The electrical conductors are typically connected to working, auxiliary, and/or other electrodes that extend into the sample chamber. The measurement device applies an input signal to the electrical conductors in the sensor strip via the electrical contacts. The electrical conductors convey the input signal via the electrodes into a sample deposited in the sample chamber. The redox reaction of the analyte generates an output signal in response to the input signal. The measurement device determines an analyte concentration in response to the output signal.

The sensor strip may include a reagent that reacts with an analyte in the biological fluid sample. The reagent may include an ionizing agent for promoting redox of the analyte, and a mediator or other substance that facilitates electron transfer between the analyte and the conductor. The ionizing agent may be an analyte-specific enzyme, such as glucose oxidase or glucose dehydrogenase, which catalyzes the oxidation of glucose in a whole blood sample. These reagents may include a binder for holding the enzyme and mediator together.

Many biosensors include one or more error detection systems to prevent or screen out analysis associated with errors. Concentration values obtained from an analysis with errors may be inaccurate. The ability to prevent or screen out these inaccurate analyses may increase the accuracy of the concentration values obtained. The error detection system may detect and compensate for errors, such as sample temperatures that differ from a reference temperature. The error detection system may detect and stop analysis of the biological fluid in response to an error, such as an underfill condition.

Some biosensors have an error detection system for detecting and compensating for the temperature of the sample. Such error detection systems typically compensate the analyte concentration for a particular reference temperature in response to the sample temperature. Some biosensor systems perform temperature compensation by varying the output signal prior to calculating the analyte concentration using a correlation equation. Other biosensor systems are temperature compensated by varying the analyte concentration calculated from the correlation equation. Biosensor systems having an error detection system for sample temperature are described in U.S. patent nos. 4,431,004; 4,750,496, respectively; 5,366,609, respectively; 5,395,504; 5,508,171, respectively; 6,391,645, respectively; and 6,576,117.

Some biosensors have an error detection system for detecting whether an underfill condition exists. Such an equal error detection system typically prevents or screens out analysis associated with insufficient volume sample size. Some underfill detection systems have one or more indicator electrodes for detecting partial and/or complete filling of the sample chamber within the sensor strip. Some biosensors have a third electrode in addition to the auxiliary and working electrodes for applying an input signal to a sample of the biological fluid. Other underfill systems use subassemblies of auxiliary electrodes to determine whether the sensor strip is underfilled. Biosensor systems having error detection systems for underfill conditions are described in U.S. Pat. Nos. 5,582,697 and 6,531,040.

Although error detection systems balance different advantages and disadvantages, they are not ideal. These systems are generally directed to detecting and responding to certain types of errors. However, these systems typically do not evaluate or determine whether the output signal from the biosensor is a normal or abnormal response from the analysis of the biological fluid. Thus, when the error detection system does not detect an error, the biosensor may provide an inaccurate analysis. Furthermore, biosensors may provide inaccurate analysis when the error detection system does not detect errors from a combination of factors that the individual factors do not contribute to the error.

To this end, there is a continuing need for improved biosensors, particularly those that may provide for the beneficial accurate and/or precise detection of abnormal output signals from the biosensors. The systems, devices, and methods of the present invention overcome at least one of the disadvantages associated with conventional biosensors.

Disclosure of Invention

The present invention provides a biosensor having an abnormal output detection system, wherein the abnormal output detection system determines whether an output signal from a redox reaction of an analyte has a normal or abnormal shape or configuration. An output signal having a normal shape or configuration may provide an accurate and/or precise analysis of the biological fluid. An output signal having an abnormal shape or configuration may not provide an accurate and/or precise analysis of the biological fluid. The biosensor generates an output signal in response to a redox reaction of the analyte. The biological fluid measures and normalizes the output signal. The biosensor compares the normalized output signal to one or more control limits and generates an error signal when the normalized output signal is not within the control limits.

A method for detecting abnormal output in a biosensor, comprising: normalizing an output signal from a redox reaction of an analyte in a sample of a biological fluid; comparing the normalized output signal to at least one control limit; and generating an error signal when the normalized output signal is not within the at least one control limit. The method may also include determining a difference between at least one baseline output value and at least one measured output value of the output signal. The output signal may be responsive to a pulsed sequence, and the at least one baseline output value may be a measured output value of the output signal. The method may further include dividing at least one output value in a pulse of the output signal by a first output value in a pulse of the output signal, and the output signal may be responsive to a gated amperometric electrochemical system. The method may further comprise determining the at least one control limit from a statistical analysis of laboratory results.

The method may include generating the output signal in response to a pulsed sequence, and the pulsed sequence may include at least five pulses. Normalized current value R of fourth pulse₄Can be represented by the following formula:

wherein i_4，1Is a first current value, i, in said fourth pulse_4，8Is the last current value in the fourth pulse. R₄May be greater than or equal to 0.45, and R₄May be less than or equal to 0.85. Normalized current value R of fifth pulse₅Can be represented by the following formula:

wherein i_5，1Is a first current value, i, in said fifth pulse_5，8Is the last current value in the fifth pulse. R₅May be greater than or equal to 0.45, and R₅May be less than or equal to 0.85. The ratio of the normalized current value of the fourth pulse to the normalized current value of the fifth pulse may be represented by:

wherein i_4，1Is a first current value, i, in said fourth pulse_4，8Is the last current value in the fourth pulse, i_5，1Is a first current value, i, in said fifth pulse_5，8Is the last current value in the fifth pulse. A ratio of the normalized current value of the fourth pulse to the normalized current value of the fifth pulse may be greater than or equal to 0.75, and may be less than or equal to 1.25.

Another method for detecting abnormal output in a biosensor, comprising: the method includes generating an output signal in response to a redox reaction of an analyte in a sample of the biological fluid, measuring the output signal, normalizing the output signal, comparing the normalized output signal to at least one control limit, and generating an error signal when the normalized output signal is not within the at least one control limit. The method may include applying an input signal to a sample of the biological fluid. The method may include intermittently measuring the output signal, and may measure at least eight current values in at least one pulse of the output signal. The method may comprise dividing at least one output value in a pulse of the output signal by a first output value in a pulse of the output signal. The method may comprise determining the at least one control limit from a statistical analysis of laboratory results.

The output signal may comprise at least five pulses, wherein the normalized current value R of the fourth pulse₄Can be represented by the following formula:

wherein i_4，1Is a first current value, i, in said fourth pulse_4，8Is the last current value in the fourth pulse. Normalized current value R of fifth pulse₅Can be represented by the following formula:

wherein i_5，1Is a first current value, i, in said fifth pulse_5，8Is the last current value in the fifth pulse. The ratio of the normalized current value of the fourth pulse to the normalized current value of the fifth pulse may be represented by:

wherein i_4，1Is a first current value, i, in said fourth pulse_4，8Is the last current value in the fourth pulse, i_5，1Is a first current value, i, in said fifth pulse_5，8Is the last current value in the fifth pulse.

The input signal may include a pulsed sequence, may be responsive to a gated amperometry electrochemical system, and/or may include a polling input signal and a test input signal. The polling input signal may have a polling pulse width of less than about 300ms, and the polling input signal may have a polling pulse interval of less than about 1 second. The polling input signal may have a polling pulse width of about 0.5ms to about 75ms and a polling pulse interval of about 5ms to about 300 ms. The test input signal may have a test pulse width of less than about 5 seconds and a test pulse interval of less than about 15 seconds. The test input signal may also have a test pulse width of about 0.1 seconds to about 3 seconds and a test pulse interval of about 0.2 seconds to about 6 seconds.

When the input signal comprises a polling input signal and a test input signal, the method may comprise: applying the polling input signal in a polling period, wherein the polling period is less than about 180 seconds; and applying the test input signal during a test period, wherein the test period is less than about 180 seconds. When the input signal comprises a polling input signal and a test input signal, the method may comprise: applying the polling input signal in a polling period, wherein the polling period is from about 0.1 seconds to about 10 seconds; and applying the test input signal during a test period, wherein the test period is from about 1 second to about 100 seconds.

When the input signal comprises a polling input signal and a test input signal, the method may comprise: applying a polling input signal to the sample for about 1.25 seconds, wherein the polling input signal has a polling pulse width of about 5-10 ms and a polling pulse interval of about 125 ms; and applying a test input signal to the sample for about 7 seconds, wherein the test input signal has a test pulse width of about 1 second and a test pulse interval of about 1.5 seconds. The polling input signal may have a potential of about 400mV, the test input signal may have a first pulse having a potential of about 400mV, and the test input signal may have at least one other pulse having a potential of about 200 mV. The test input signal may be applied when the polling output signal is greater than or equal to a polling threshold, and the polling threshold may be about 250 nA.

A biosensor for determining an analyte concentration in a biological fluid, comprising: a sensor strip having a sample interface located on a substrate, wherein the sample interface is adjacent to a reservoir formed by the substrate; a measurement device having a processor connected to a sensor interface, wherein the sensor interface is in electrical communication with the sample interface, the processor normalizes an output signal from a redox reaction of an analyte in a sample of a biological fluid, the processor compares the normalized output signal to at least one control limit, and the processor generates an error signal when the normalized output signal is not within the at least one control limit. The processor may determine a difference between at least one baseline output value and at least one measured output value of the output signal, and/or may divide at least one of the output values in a pulse of the output signal by a first one of the output values in a pulse of the output signal. The at least one control limit may be predetermined from a statistical analysis of laboratory results.

The processor may apply an input signal to the sample of biological fluid, wherein the input signal includes a polling input signal and a test input signal. The polling input signal may have a polling pulse width of less than about 300ms and a polling pulse interval of less than about 1 second. The test input signal may have a test pulse width of less than about 5 seconds and a test pulse interval of less than about 15 seconds. The processor may apply the polling input signal in a polling period of less than about 180 seconds and may apply the test input signal in a test period of less than about 180 seconds. The processor may apply the polling input signal for a polling period of about 0.1 seconds to about 10 seconds, and may apply the test input signal for a test period of about 1 second to about 100 seconds. The processor may apply a polling input signal to the sample for about 1.25 seconds, wherein the polling input signal has a polling pulse width of about 5-10 ms, a polling pulse interval of about 125ms, and a potential of about 400 mV. The processor applies a test input signal to the sample for about 7 seconds, wherein the test input signal has a test pulse width of about 1 second, a test pulse interval of about 1.5 seconds, a first pulse at a potential of about 400mV, and at least one other pulse at a potential of about 200 mV. The processor may apply the test input signal when the polling output signal is greater than or equal to a polling threshold of about 250 nA.

The output signal of the biosensor may include at least five pulses, and the normalized current value R of the fourth pulse₄Can be represented by the following formula:

wherein i_4，1Is a first current value, i, in said fourth pulse_4，8Is the last current value in the fourth pulse. Normalized current value R of fifth pulse₅Can be represented by the following formula:

wherein i_5，1Is a first current value, i, in said fifth pulse_5，8Is the last current value in the fifth pulse. The ratio of the normalized current value of the fourth pulse to the normalized current value of the fifth pulse may be represented by:

wherein i_4，1Is a first current value, i, in said fourth pulse_4,8Is the last current value in the fourth pulse, i_5，1Is a first current value, i, in said fifth pulse_5，8Is the last current value in the fifth pulse.

The processor of the biosensor may measure the output signal. The processor may intermittently measure the output signal. The output signal may be responsive to a pulsed sequence. The output signal may be responsive to a gated amperometric electrochemical system.

Drawings

The invention can be better understood with reference to the following drawings and description. The components in the figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. Moreover, in the figures, corresponding parts are designated by the same reference numerals throughout the different views.

FIG. 1 represents a method for detecting an abnormal output signal in a biosensor;

FIG. 2 shows a graph of output signal versus input signal for an electrochemical system using gated amperometry;

fig. 3 depicts a schematic diagram of a biosensor with an abnormal output signal detection system.

Detailed Description

The invention provides an abnormal output detection system for a biosensor. The abnormal output detection system improves the accuracy and precision of the biosensor in determining whether the output signal has a shape or configuration that may not provide accurate and/or precise analysis of the biological fluid. The biosensor generates an output signal in response to a redox reaction of the analyte. The output signal may measure and correlate to an analyte concentration in the biological fluid. The biosensor normalizes the output signal and compares the normalized output signal to one or more control limits. The biosensor generates an error signal when the normalized output signal is not within the control limit. The abnormal output detection system may be used alone or in conjunction with other error detection systems. Biosensors may be used to measure one or more analyte concentrations, such as glucose, uric acid, lactate, cholesterol, bilirubin, and the like, in biological fluids, such as whole blood, urine, saliva, and the like.

Fig. 1 represents a method for detecting abnormal output from a biosensor. The normal output signal has a shape or configuration that provides accurate and/or precise analysis of the biological fluid. The abnormal output signal has a shape or configuration that may not provide an accurate and/or precise analysis of the biological fluid. 102, the biosensor generates an output signal in response to a redox reaction of an analyte in a sample of the biological fluid. In 104, the biosensor measures the output signal. In 106, the biosensor normalizes the output signal. In 108, the biosensor compares the normalized output signal to one or more control limits. At 110, the biosensor generates an error signal when the normalized output signal is not within the control limit.

At 102 of fig. 1, the biosensor generates an output signal in response to an oxidation/reduction or redox reaction of an analyte in a sample of the biological fluid. Optical sensor systems, electrochemical sensor systems, and the like may be used to generate the output signal.

Optical sensor systems typically measure the amount of light absorbed or produced by the reaction of a chemical indicator with an analyte redox reactant. Enzymes may be included in the chemical indicator to enhance reaction kinetics. The output signal or light of the optical system may be converted into an electrical signal such as a current or potential.

In light-absorbing optical systems, chemical indicators produce light-absorbing reaction products. Chemical indicators such as tetrazolium salts may be used in conjunction with enzymes such as diaphorase. Tetrazolium salts typically generate formazan (a chromogen) in response to the redox reaction of the analyte. An incident excitation beam from a light source is directed to the sample. The light source may be a laser, a light emitting diode, or the like. The incident light beam may have a wavelength selected to facilitate absorption by the reaction products. When an incident light beam passes through the sample, the reaction products absorb a portion of the incident light beam, thereby attenuating or reducing the intensity of the incident light beam. The incident beam may be reflected back from the sample to the detector or transmitted through the sample to the detector. The detector collects and measures the attenuated incident beam (output signal). The amount of light attenuated by the reaction product is indicative of the concentration of analyte in the sample.

In optical systems that generate light, the chemical indicator fluoresces or emits light in response to an analyte redox reaction. The detector collects and measures the light generated (output signal). The amount of light generated by the chemical indicator is indicative of the concentration of the analyte in the sample.

The electrochemical system applies an input signal to the biological fluid sample. The input signal may be a potential or a current and may be constant, varying, or a combination thereof, for example when an AC signal with a DC signal offset is applied. The input signal may be applied in the form of a single or multiple pulses, a sequence or a cycle. The analyte will undergo a redox reaction when an input signal is applied to the sample. Enzymes or the like may be used to enhance the redox reaction of the analyte. Mediators can be used to maintain the oxidation state of the enzyme. The redox reaction produces an output signal that can be measured continuously or periodically during transient output and/or steady state output. Various electrochemical methods can be used, such as amperometry, coulometry, voltage analysis, and the like. Gated amperometry and gated voltammetry may also be used.

In amperometry, a potential or voltage is applied to the biological fluid sample. The redox reaction of the analyte generates an electrical current in response to the electrical potential. The current is measured over time to quantify the analyte in the sample. Amperometry typically measures the rate at which an analyte is oxidized or reduced to determine the concentration of the analyte in a sample. Biosensor systems using amperometry are described in U.S. patent nos. 5,620,579, 5,653,863, 6,153,069 and 6,413,411.

In coulometry, a potential is applied to a sample of biological fluid to thoroughly oxidize or reduce the analyte within the sample. The potential generates a current that is integrated over the oxidation/reduction time, thereby generating a charge that is representative of the analyte concentration. Coulometry typically yields the total amount of analyte within a sample. A biosensor system using coulometry for whole blood glucose measurement is described in us patent No.6,120,676.

In voltage analysis methods, a varying potential is applied to a biological fluid sample. The redox reaction of the analyte generates an electrical current in response to the applied potential. The current is measured over time to quantify the analyte in the sample. Voltage analysis methods typically measure the rate at which an analyte is oxidized or reduced to determine the concentration of the analyte in a sample. The Methods available in "Electrochemical Methods" by a.j.bard and l.r.faulkner in 1980: additional information on voltage analysis is found in fundametals and Applications.

In gated amperometry and gated voltammetry, pulsed excitation was used, as described in U.S. provisional patent application No.60/700,787, filed on 7/20/2005 and U.S. provisional patent application No.60/722,584, filed on 9/30/2005, respectively, both of which are incorporated herein by reference.

Figure 2 shows a graph of output signal versus input signal for an electrochemical system using gated amperometry. The input signal is a potential applied to a sample of the biological fluid. The input signals include a polling input signal and a test input signal. The output signal is the current generated from the sample. The output signals include a polling output signal and a test output signal. The sample is responsive to a test input signal to produce a test output signal from a redox reaction of glucose in whole blood. The input and output signals are useful for biosensors having a working electrode and an auxiliary electrode. Other biosensors may be used, including those with additional electrodes and different structures. Other analyte concentrations may be measured, including those in other biological fluids. Other output signals may be generated, including those that may initially fall and those that may fall in all pulses.

The test output signal in fig. 2 has a normal shape or configuration. The current value in the first pulse increases from the first to the last current value. The current values in the second to fifth pulses decrease or decay from the first to the last current value in each pulse. The abnormal shape or configuration includes a current value increased in any one of the second to fifth pulses. The abnormal shape or configuration includes a current value that decreases or decays too rapidly (steeper slope) or too slowly (flatter slope). Other abnormal shapes and configurations may occur.

In use, a sample of the biological fluid is deposited in the biosensor. The biosensor applies a polling signal to the sample from about-1.25 seconds to about 0 seconds. The pulses have a pulse width of about 5-10 ms and a pulse interval of about 125 ms. The biosensor generates a polling output signal in response to a polling input signal. The biosensor measures the polling output signal. The biosensor may have a potentiostat for providing a polling output signal to an input of the analog comparator.

The biosensor applies the test input signal to the electrode from about 0 seconds to about 7 seconds when the polling output signal is equal to or greater than the polling threshold. The polling threshold may be approximately 250 nA. The comparator may compare the polling threshold to the polling output signal. The output signal of the comparator may trigger the launch of the test input signal when the polling output signal exceeds a polling threshold.

During the test input signal, the biosensor applies a first pulse having a potential of about 400mV for a time of about 1 second to the working electrode and the auxiliary electrode. The first pulse then relaxes for 0.5 seconds, which may be a substantially open circuit, etc. The test output signal or current within the first pulse is measured and stored in a memory device. The biosensor may apply a second pulse of about 200mV potential to the working electrode and the counter electrode for a period of about 1 second. The test output signal or current within the second pulse is measured and stored in a memory device. The biosensor continues to apply pulses from the test input signal to the working electrode and the auxiliary electrode until the end of the test period or as required by the biosensor. The test period may be about 7 seconds. The biosensor may measure and store the test output signal or current within each pulse.

The polling input signal is an electrical signal, such as a current or potential, that is pulsed or turned on and off at a set frequency or interval. The sample generates a polling output signal in response to a polling input signal. The polling output signal is an electrical signal, such as a current or a potential. The biosensor may display the polling output signal on a display and/or may store the test output signal in a memory device. The biosensor may apply a polling signal to detect when the sample is connected to the electrode. Biosensors may use other methods and devices to detect when a sample is available for analysis.

The polling input signal is a sequence of polling pulses separated by a polling relaxation. During the polling pulse, the electrical signal is on. During the polling relaxation, the electrical signal is off. Switching on may include a time period when an electrical signal is present. The switch-off may include a time period when no electrical signal is present. The shutdown may not include a time period when substantially no magnitude of electrical signal is present. The electrical signal may be switched on and off by closing and opening the circuit, respectively. The circuit may be opened and closed mechanically, electrically, or the like.

The polling input signal may have one or more polling pulse intervals. The polling pulse interval is the sum of the polling pulse and the polling relaxation. Each polling pulse has an amplitude and a polling pulse width. The amplitude indicates the intensity of the potential, current or similar property of the electrical signal. The amplitude may change during the polling pulse or be constant. The polling pulse width is the duration of the polling pulse. The polling pulse width in the polling input signal may vary or be substantially the same. Each polling relaxation has a polling relaxation width, which is the time duration of the polling relaxation. The polling relaxation widths in the polling input signal may change or be substantially the same.

The polling input signal may have a polling pulse width of less than about 300 milliseconds (ms) and a polling pulse interval of less than about 1 second. The polling input signal may have a polling pulse width of less than about 100ms and a polling pulse interval of less than about 500 ms. The polling input signal may have a polling pulse width of about 0.5ms to about 75ms and a polling pulse interval of about 5ms to about 300 ms. The polling input signal may have a polling pulse width of about 1ms to about 50ms and a polling pulse interval of about 10ms to about 250 ms. The polling input signal may have a polling pulse width of about 5ms and a polling pulse interval of about 120 ms. The polling input signal may have other widths and pulse intervals.

The biosensor may apply a polling input signal to the sample during a polling period. The polling period may be less than about 15 minutes, 5 minutes, 2 minutes, or 1 minute. The polling period may be longer depending on how the user uses the biosensor. The polling period may be from about 0.5 seconds (sec) to about 15 minutes. The polling period may be from about 5 seconds to about 5 minutes. The polling period may be from about 10 seconds to about 2 minutes. The polling period may be about 20 seconds to about 60 seconds. The polling period may be about 30 to about 40 seconds. The polling period may have less than about 200, 100, 50, or 25 pulse intervals. The polling period may have a pulse interval of about 2 to about 150. The polling period may have a pulse interval of about 5 to about 50. The polling period may have a pulse interval of about 5 to about 15. The polling period may have about 10 pulse intervals. Other polling periods may be used.

The biosensor applies the test input signal when the polling output signal is equal to or greater than the polling threshold. The polling threshold may be greater than about 5% of the expected test input signal at the beginning of the first pulse. The polling threshold may be greater than about 15% of the expected test input signal at the beginning of the first pulse. The polling threshold may be about 5% to about 50% of the expected test input signal at the beginning of the first pulse. Other polling thresholds may be used. The biosensor may indicate on the display that the polling output signal is equal to or greater than the polling threshold.

The test input signal is an electrical signal such as a current or potential that is pulsed or turned on and off at a set frequency or interval. The sample generates a test output signal in response to the test input signal. The test output signal is an electrical signal such as a current or potential.

The test input signal is a sequence of test pulses separated by a test relaxation. During the test pulse, the electrical signal is on. During test relaxation, the electrical signal is off. The switch-on is a time period that includes when the electrical signal is present. The switch-off includes time periods when no electrical signal is present and does not include time periods when substantially no magnitude electrical signal is present. The electrical signal is switched on and off by closing and opening the circuit, respectively. The circuit may be opened and closed mechanically, electrically, or the like.

The test input signal may have one or more test pulse intervals. The test pulse interval is the sum of the test pulse and the test relaxation. Each test pulse has an amplitude and a test pulse width. Amplitude is an intensity that indicates a potential, a current, or a similar property of an electrical signal. The amplitude may change during the test pulse or be constant. The test pulse width is the time duration of the test pulse. The test pulse width in the test input signal may vary or be substantially the same. Each test relaxation has a test relaxation width, which is the time duration of the test relaxation. The test relaxation widths in the test input signal may vary or be substantially the same.

The test input signal may have a test pulse width of less than about 5 seconds and a test pulse interval of less than about 15 seconds. The test input signal may have a test pulse width of less than about 3, 2, 1.5, or 1 seconds and a test pulse interval of less than about 13, 7, 4, 3, 2.5, or 1.5 seconds. The test input signal may have a test pulse width of about 0.1 seconds to about 3 seconds and a test pulse interval of about 0.2 seconds to about 6 seconds. The test input signal may have a test pulse width of about 0.1 seconds to about 2 seconds and a test pulse interval of about 0.2 seconds to about 4 seconds. The test input signal may have a test pulse width of about 0.1 seconds to about 1.5 seconds and a test pulse interval of about 0.2 seconds to about 3.5 seconds. The test input signal may have a test pulse width of about 0.4 seconds to about 1.2 seconds and a test pulse interval of about 0.6 seconds to about 3.7 seconds. The test input signal may have a test pulse width of about 0.5 seconds to about 1.5 seconds and a test pulse interval of about 0.75 seconds to about 2.0 seconds. The test input signal may have a test pulse width of about 1 second and a test pulse interval of about 1.5 seconds. The test input signal may have other widths and pulse intervals.

The biosensor applies a test input signal to the sample during the test. The test period may have the same or a different duration than the polling period. The test period of the test input signal may be less than approximately 180, 120, 90, 60, 30, 15, 10, or 5 seconds. The test period may be from about 1 second to about 100 seconds. The test period may be from about 1 second to about 25 seconds. The test period may be about 1 second to about 10 seconds. The test period may be about 2 seconds to about 3 seconds. The test period may be about 2.5 seconds. The test period may have less than about 50, 25, 20, 15, 10, 8, 6, or 4 test pulse intervals. The test period may have a test pulse interval of about 2 to about 50. The test period may have a test pulse interval of about 2 to about 25. The test period may have a test pulse interval of about 2 to about 15. The test period may have about 10 test pulse intervals. Other test periods may be used.

At 104 of fig. 1, the biosensor measures an output signal generated by a redox reaction of an analyte in a sample. The biosensor may measure the output signal continuously or intermittently. For example, the biosensor intermittently measures the test output signal in each pulse of fig. 2, thereby generating eight current values in each pulse. The sample generates a test output signal in response to a redox reaction of an analyte in the biological fluid and the test input signal. The biosensor may display the test output signal on a display and/or may store the test output signal in a memory device. The biosensor may determine the analyte concentration in the sample from the output signal.

At 106 of fig. 1, the biosensor normalizes the test output signal. The normalized output signal may improve the comparison of test output signals having different magnitudes due to the amount of analyte in the sample of the biological fluid. In general, a larger amount of analyte in a sample produces a higher magnitude output signal than a smaller amount of analyte. The normalized output signal may also improve the mathematical evaluation of the shape or configuration of the output signal to determine whether the output signal is normal or abnormal. The normalized output signal may allow the same control limits to be used over a wide range of glucose and hematocrit levels.

To normalize the test output signal, the biosensor determines a difference between one or more baseline output values and measured output values of the test output signal. The difference may be an arithmetic difference between the baseline output value and the test output value. The difference may be a ratio of the baseline output signal to the test output signal. Other differences may be used. The baseline output value may be selected from a statistical analysis of laboratory results or predetermined. The baseline output value may be one or more of the measured output values of the test output signal. A single baseline output value may be used for the test output signal. Multiple baseline output values may be used, such as different baseline output values for each pulse in the test output signal.

In a pulsed sequence, such as gated amperometry or gated voltage analysis, the assay output values may be normalized by dividing all output values in the pulse by the first output value in the pulse. The other output value in each pulse may be a baseline output value. In a single pulse or similar sequence, the measured output value may be normalized by dividing all output values in the pulse by the first or another output value. Other normalization methods may be used.

Table 1 shows the first and last current values for the pulses from the gated amperometry sequence of fig. 2. The normalized current value is the ratio of the measured current value to the baseline current value. The baseline current value is the first current value in each pulse. The normalized current value mathematically indicates that the shape or configuration of the output signal exhibits an increase from the first to the last current value in the first pulse. The normalized current value mathematically indicates that the shape or configuration of the output signal exhibits a decrease from the first to the last current value in the first pulse.

TABLE I

	Measured current value	Baseline current value	Normalized current value (measurement/base)
				Pulse 1, first Current value (i)1，1)	2,500nA	2,500nA	1.0
Pulse 1, final current value (i)1,8)	10,000nA	2,500nA	4.0
				Pulse 2, first Current value (i)2,1)	20,000nA	21,000nA	1.0
Pulse 2, final current value (i)2,8)	18,000nA	21,000nA	0.86
				Pulse 3, first Current value (i)3，1)	20,000nA	22,000nA	1.0
Pulse 3, final currentValue (i)3，8)	17,000nA	22,000nA	0.77
				Pulse 4, first Current value (i)4，1)	24,000nA	24,000nA	1.0
Pulse 4, final current value (i)4，8)	15,000nA	24,000nA	0.63
				Pulse 5, first Current value (i)5，1)	20,000nA	20,000nA	1.0
Pulse 5, final current value (i)5，8)	14,000nA	20,000nA	0.70

At 108 of fig. 1, the biosensor compares the normalized output signal to one or more control limits. The control limit is a mathematical representation of a threshold value where the shape or configuration of the output signal transitions from normal to abnormal. The control limits may be selected or predetermined to apply to all or a particular portion of the output signal. The particular portion of the output signal includes one or more pulses, one or more output values in each pulse or a particular pulse, and so forth. Different control limits may be used for different parts of the output signal. Different control limits may be used for different ranges of glucose, hematocrit, etc. The control limit may be selected or predetermined to apply to the normalized output signal for a particular output signal value in a particular pulse. The control limits may be selected or predetermined to apply to the mathematical relationship between the output signal values in the different pulses. The control limits may be selected to further define a desired shape or configuration of the output signal. The control limits may be predetermined from statistical or similar analysis of laboratory results. Other control limits may be used.

In the test output signal of FIG. 2Normalized current value (R) for the last pulse of the fourth pulses₄) Normalized current value (R) of the last pulse of the fifth pulses₅) And R₄The Ratio (Ratio) to R5, the control limit is selected or predetermined. Although control limits for the fourth and fifth pulses are used, other control limits may be used, including those for the fourth and fifth pulses and those for other pulses in the test output signal.

Normalized current value (R) of last pulse of fourth pulses₄) Can be represented by the following formula:

the values of table 1 were substituted for formula (1) to give:

normalized current value (R) of the last pulse of the fifth pulses₅) Can be represented by the following formula:

the values of table 1 were substituted for formula (2) to give:

normalized current value (R) of last pulse of fourth pulses₄) Normalized current value (R) with the last pulse of the fifth pulses₅) The ratio of (d) can be represented by the following formula:

simplifying the formula (3) to obtain:

the values of table 1 were substituted for formula (4) to give:

for R₄、R₅And Ratio are shown in table II. R₄、R₅And Ratio is within applicable control limits, indicating that the test output signal of FIG. 2 has a normal shape or configuration. Other control limits may be used.

TABLE II

	Description of the invention	Value of
			R4min	R4Minimum limit	0.45
R4max	R4Maximum limit	0.85
			R5min	R5Minimum limit	0.45
R5max	R5Maximum limit	0.85
			Ratiomin	Ratio minimum limit	0.75
Ratiomax	Ratio maximum limit	1.25

The control limit is selected based on normalized current readings from greater than 9,000 blood samples. Each blood sample is introduced onto a freshly prepared or matured sensor strip placed in the measurement device. Current readings are taken from the sensor strip at a sample temperature of about 10 ℃ to about 40 ℃. The blood sample has a glucose concentration of about 10mg/dL to about 600mg/dL and a hematocrit concentration of about 20% to about 55%. The normalized current values from each analysis are separated into known good and bad values based on the underlying current distribution. The control limits are selected using standard statistical techniques to include acceptable variation on the mean of good values.

At 110 of fig. 1, the biosensor generates an error signal in response to the normalized output signal not being within the control limits. The error signal may be displayed on the display device and/or resident in the memory device. The biosensor may provide an error signal during or after the analysis of one or more analytes in the sample is performed. The biosensor may provide an error signal immediately after detection and may stop analysis of the analyte. The biosensor may not provide the concentration of the analyte in response to the error signal.

Fig. 3 depicts a schematic diagram of a biosensor 300 having an abnormal output signal detection system. The biosensor 300 determines the analyte concentration in a sample of the biological fluid. As previously described, the abnormal output detection system indicates when the shape or configuration of the output signal may provide an inaccurate and/or imprecise analysis of one or more analytes. Biosensor 300 includes a measurement device 302 and a sensor strip 304, which may be implemented as a desktop device, a portable or handheld device, or the like. The measurement device 302 and the sensor strip 304 may be adapted to implement an electrochemical sensor system, an optical sensor system, combinations thereof, or the like. The abnormal output detection system may improve the accuracy and/or precision of the biosensor 300 in determining when an abnormal output signal occurs. The biosensor 300 may be used to determine one or more analyte concentrations, such as glucose, uric acid, lactate, cholesterol, bilirubin, and the like, in a biological fluid, such as whole blood, urine, saliva, and the like. Although a particular configuration of biosensor 300 is shown, it may have other configurations, including configurations with other components.

The sensor strip 304 has a substrate 306 forming a reservoir 308 and a channel 310 with an opening 312. The reservoir 308 and the channel 310 may be covered by a cap with a vent. The reservoir 308 defines a partially enclosed volume (cap gap). The reservoir 308 may contain a component that helps retain a liquid sample (e.g., a water-swellable polymer or porous polymer matrix). The reagent may be deposited in the reservoir 308 and/or the channel 310. The reagents may include one or more enzymes, binders, mediators and other reactive or non-reactive species. The reagent may include a chemical indicator for the optical system. The sensor strip 304 may also have a sample interface 314 disposed adjacent to the reservoir 308. The sample interface 314 may partially or completely surround the reservoir 308. The sensor strip 304 may have other configurations.

The sample interface 314 has conductors that connect to the working electrode and the counter electrode. The electrodes may lie substantially in the same plane. The electrodes may be spaced more than 200 μm or 250 μm apart and may be spaced at least 100 μm from the cover. The electrodes may be disposed on a surface of the substrate 306 forming the reservoir 308. The electrodes may extend or be inserted into the cap gap formed by the reservoir 308. The dielectric layer may partially cover the conductor and/or the electrode. The sample interface 314 may have other electrodes and conductors. The sample interface 314 may have one or more light inlets or openings for viewing the sample. The sample interface 314 may have other components and configurations.

The measurement device 302 includes circuitry 316 coupled to a sensor interface 318 and a display 320. Circuitry 316 includes a processor 322 coupled to a signal generator 324 and a storage medium 328. The measurement device may have other components and configurations.

The signal generator 324 provides an electrical input signal to the sensor interface 318 in response to the processor 322. The electrical input signals may include polling and test input signals used in an abnormal output detection system. The electrical input signals may include electrical signals for operating or controlling the detectors and light sources in the sensor interface 318 for the optical detector system. The electrical input signal may be transmitted by the sensor interface 318 to the sample interface 314. The electrical input signal may be a potential or a current and may be constant, varying, or a combination thereof, for example when an AC signal with a DC signal offset is applied. The electrical input signal may be applied in the form of a single or multiple pulses, sequences or periods. The signal generator 324 may also record signals from the sensor interface 318 as a generator-recorder.

The storage medium 328 may be magnetic, optical, or semiconductor memory, other computer readable storage devices, or the like. The storage medium 328 may be a fixed storage device or a removable storage device such as a memory card.

Processor 322 implements anomaly output detection, analyte analysis, and data processing using computer readable software code and data stored in storage medium 328. Processor 322 may initiate anomalous output detection and analyte analysis in response to the presence of sensor strip 304 at sensor interface 318, application of a sample onto sensor strip 304, user input, and the like. The processor 322 instructs the signal generator 324 to provide the electrical input signal to the sensor interface 318.

The processor 322 receives and measures the output signal from the sensor interface 318. The output signal may be an electrical signal, such as a current or potential, or light. The output signals may include polling and test output signals. The output signal may include a test output signal generated in response to a redox reaction of an analyte in the sample. The output signal may be generated using an optical system, an electrochemical system, or the like. Processor 322 may compare one or more polling thresholds to the polling output signal. Processor 322 can measure the test output signal and correlate it to the analyte concentration in the sample. As previously described, the processor 322 may normalize the test output signal and compare one or more control limits to the normalized signal.

When the normalized output signal is not within the control limits, i.e., the test output signal is not normal in shape or configuration, the processor 322 provides an error signal for the abnormal output. Processor 322 may display the error signal on display 320 and may store the error signal and associated data in storage medium 328. Processor 322 can provide an error signal at any time during or after the analyte analysis.

Processor 322 determines the analyte concentration from the test output signal. The results of the analyte analysis are output to display 320 and may be stored in storage medium 328. Instructions for performing analyte analysis may be provided by computer readable software code stored in storage medium 328. The code may be object code or any other code that describes or controls the functions described herein. The data from the analyte analysis may be subjected to one or more data processing in processor 322, including determining decay rate, K-constant, slope, intercept, and/or sample temperature.

The sensor interface 318 has contacts that connect or electrically communicate with conductors in the sample interface 314 of the sensor strip 304. The sensor interface 318 transmits the electrical input signal from the signal generator 324 to the connector in the sample interface 314 via these contacts. The sensor interface 318 also transmits output signals from the sample interface 314 to the processor 322 and/or the signal generator 324. The sensor interface 318 may also include detectors, light sources, and other components used in optical sensor systems.

The display 320 may be of an analog or digital type. The display may be an LCD display adapted to display the value readings. Other displays may be used.

In use, a liquid sample of the biological fluid is transferred into the cap gap formed by the reservoir 308 by introducing the liquid into the opening 312. The liquid sample flows into the reservoir 308 via the channel 310, filling the cap gap while venting the previously contained air. The liquid sample chemically reacts with reagents deposited in the channel 310 and/or reservoir 308.

Processor 322 detects when a sample of the biological fluid is available for analysis. The sensor strip 304 is positioned adjacent to the measurement device 302. The proximity location includes a location that places sample interface 314 in electrical and/or optical communication with sensor interface 318. Electrical communication includes the transfer of input and/or output signals between contacts in the sensor interface 318 and conductors in the sample interface 314. Optical communication includes the transfer of light between a light inlet in the sample interface 314 and a detector in the sensor interface 318. Optical communication also includes the transfer of light between a light inlet in the sample interface 314 and a light source in the sensor interface 318.

The processor 322 may direct the signal generator 324 to provide a polling input signal to the sensor interface 318, which applies the polling input signal to the sample via the electrodes in the sample interface 314. The sample generates a polling output signal in response to a polling input signal. The sample interface 314 provides a polling output signal to the sensor interface 318. The processor 322 receives the polling output signal from the sensor interface 318. The processor 322 may display the polling output signal on the display 320 and/or may store the polling output signal in the storage medium 328.

The processor 322 may direct the signal generator 324 to provide a test input signal to the sensor interface 318 when the polling output signal is equal to or greater than the polling threshold. The processor 322 may have a comparator circuit to provide a test input signal to the sensor interface 318 when the polling output signal is equal to or greater than the polling threshold. In the comparator circuit, the polling output signal is directed to the input of an electrical (analog) comparator or the like. The comparator compares the polling output signal to a polling threshold. The output of the comparator triggers the launch of the test input signal when the polling output signal is equal to or greater than the polling threshold.

The sensor interface 318 applies a test input signal to the sample via the sample interface 314 during testing. The sample generates a test output signal in response to the test input signal. Sample interface 314 provides the test output signal to sensor interface 318.

The processor 322 receives the test output signal from the sensor interface 318. Processor 322 measures the test output signal generated by the sample. Processor 322 determines the analyte concentration of the sample in response to the test output signal. Processor 322 may display the test output signal on display 320 and/or may store the test output signal in storage medium 328. As previously described, the processor 322 normalizes the test output signal. The processor 322 compares the normalized output signal to one or more control limits during the test period. When the normalized output signal is not within the control limits, the processor 332 provides an error signal of the abnormal output. The error signal may be displayed on the display 320 and/or resident in the storage medium 328. Processor 322 may provide an error signal immediately or at another time, such as after the analyte is analyzed.

Without intending to be limited in scope, application, or implementation, the following algorithms may be used to implement the foregoing methods and systems:

step 1: switching on the biosensor power supply

Step 2: performing biosensor self-testing

And step 3: set Polling, apply sample to sensor

Setting ASIC polling potential to v_poll

Setting ASIC threshold level to i_trigger

Setting the poll period timer to be at int_pollTerm of treatment

And 4, step 4: arrangement of sensor currents for testing

Waiting for a poll period timer to expire

Start ASIC Charge Pump (charge pump)

Making ASIC threshold detector (i)_tngger) Function is realized

Make polling potential (v)_poll) Function is realized

Selecting sensor channels for applying potentials to sensors

Wait to set time t_poll

And 5: testing whether sensor current exceeds a threshold

Step 6: delaying and retesting sensor current

And 7: detection of sample application

Time to start counting

Starting pulse sequence

And 8: pulse 1-measuring sensor current i_1，1And i_1，8

At t_p1At that time, pulse 1 starts

Setting pulse 1 duration to d_p1

Setting the pulse 1 sensor potential to v_p1

Selecting sensor channels for applying potentials to sensors

At t_1，1At the moment, the sensor signal is measured and the value is stored as AD_S11

At t_1，8At the moment, the sensor signal is measured and the value is stored as AD_S18

And step 9: delay 1-renormalization electronics

In AD₂At the end of the reading, delay 1 begins, and the sensor channel is disconnected

At the beginning of pulse 2, delay 1 ends

Setting the potential to V_standardize

At t_c1At the time, the reference resistor channel is selected and the signal is measured and the value stored as

AD_R1

At t_c2At the time, an offset channel is selected and the signal is measured, the value is stored as AD_o1

Remarking: the sensor current starting at pulse 1 is from AD_R1And AD_o1Calculate out

Coming from

Step 10: pulse 2-measuring sensor current i_2，1And i_2,8

At t_p2At that time, pulse 2 starts

Setting pulse 2 duration to d_p2

General pulsePotential of the sensor 2 is set to v_p2

Selecting sensor channels for applying potentials to sensors

At t_2,1At the moment, the sensor signal is measured and the value is stored as AD_S21

At t_2,8At the moment, the sensor signal is measured and the value is stored as AD_S28

Step 11: delay 2-

In AD_S3At the end of the reading, delay 2 begins and the sensor channel is disconnected

At the beginning of pulse 3, delay 2 ends

Selecting an offset channel to disconnect the sensor

Step 12: pulse 3-measurement of sensor current: i.e. i_3,1And i_3，8

At t_p3At that time, pulse 3 starts

Pulse 3 duration is set to d_p3

Setting the pulse 3 sensor potential to v_p3

Selecting sensor channels for applying potentials to sensors

At t_3,1At the moment, the sensor signal is measured and the value is stored as AD_S31

At t_3,8At the moment, the sensor signal is measured and the value is stored as AD_S38

Step 13: delay 3-T₁And i_wet

In AD_S38At the end of the reading, delay3 Start, disconnect sensor channel

At the beginning of pulse 4, delay 3 ends

Setting the potential to V_standardize

At t_c3At that time, the thermistor channel is selected and the signal is measured and the value stored as ADT₁

At t_wetAt the time, an offset channel is selected and the signal is measured, the value is stored as AD_wet

Step 14: pulse 4-measurement of sensor current: i.e. i_4，1、i_4，4And i_4，8

At t_p4At that time, pulse 4 starts

Pulse 4 duration is set to d_p4

Setting the pulse 4 sensor potential to v_p4

Selecting a sensor channel to apply a potential to a sensor

At t_4,1At the moment, the sensor signal is measured and the value is stored as AD_S41

At t_4,4At the moment, the sensor signal is measured and the value is stored as AD_S44

At t_4，8At the moment, the sensor signal is measured and the value is stored as AD_S48

Step 15: delay 4-

In AD_S48At the end of the reading, delay 4 begins, and the sensor channel is disconnected

At the beginning of pulse 5, delay 4 ends

Selecting an offset channel to disconnect the sensor

Step 16: pulse 5-measurement of sensor current: i.e. i_5，1、i_5，4And i_5，8

At t_p5At that time, pulse 5 starts

Setting pulse 5 duration to d_p5

Setting the pulse 5 sensor potential to v_p5

Selecting a sensor channel to apply a potential to a sensor

At t_5，1At the moment, the sensor signal is measured and the value is stored as AD_S51

At t_5，4At the moment, the sensor signal is measured and the value is stored as AD_S54

At t_5，8At the moment, the sensor signal is measured and the value is stored as AD_S58

Disabling ASIC analog functions

And step 17: calculating the ratio

Computing

Computing

Computing

Step 18: finding the slope and intercept of the calibration numbers for a batch

S = slope value of calibration number for current batch

Int = intercept value of calibration number for current batch

Step 19: adjusting slope and intercept for temperature effects

Step 20: calculating the glucose concentration at 25 deg.C

Step 21: conversion to target reference value (plasma vs. WB reference value)

Step 22: checking for under-quantity

Step 23: checking for ratios for "abnormal behavior"

If (R)₄>R4_maxOr

R₄<R4_minOr

R₅>R5_maxOr

R₅<R5_minOr

Ratio<Ratio_min) Then, then

Start of

If (Errorcode is not set), then

ErrorCode is set to "abnormal behavior"

End up

Step 24: if the glucose is low, the ratio is checked again for "abnormal behavior"

If (G)_25C<G_1im) Then, then

Start of

If (R)₄<R4L_maxOr

R₄<R4L_minOr

R₅>R5L_maxOr

R₅<R5L_minOr

Ratio>RatioL_maxOr

Ratio<RatioL_min) Then, then

Start of

If (Errorcode is not set), then

ErrorCode is set to "abnormal behavior"

End up

Step 25: examination of Limit glucose levels

Step 26: display the results

The algorithm may have other subroutines, including those for checking for errors such as sample temperature and underfill conditions. The constants that can be used in the above algorithm are listed in table III and table IV below. Other constants may also be used.

TABLE III

Constant number	Description of the invention	Value of	Unit of
				vpoll	Polling voltage	400	mV
intpoll	Polling interval	125	ms
				tpoll	Duration of polling	10	Minute (min)
itrigger	Threshold detection trigger current	250	nA
				tp1	Pulse 1 start time	0	sec
dp1	Pulse 1 duration	1	Second of
				vp1	Pulse 1 voltage level	400	mV
t1，1	Moment of sensor current reading 1 (only 7-sec)	0.125	sec
				t1，8	Moment of sensor current reading 2 (only 7-sec)	1.00	sec
tc1	Offset reading time	1.125	sec
				tc2	Reference reading time	1.25	sec
tp2	Pulse 2 start time	1.5	sec
				dp2	Duration of pulse 2	1	Second of
vp2	Pulse 2 voltage level	200	mV
				t2，1	Moment of sensor current reading 3	1.625	sec
t2，8	Moment of sensor current reading 4	2.50	sec
				tp3	Pulse 3 Start time (only 7-sec)	3	sec
dp3	Pulse 3 duration (only 7-sec)	1	Second of
				vp3	Pulse 3 voltage level (only 7-sec)	200	mV
t3，1	Moment of sensor current reading 5 (only 7-sec)	3.125	sec
				t3，8	Moment of sensor current reading 6 (only 7-sec)	4.00	sec
tc3	Thermistor reading time	4.125	sec
				twet	Wet sensor current reading time	4.25	sec
tp4	Pulse 4 Start time (only 7-sec)	4.5	Second of
				dp4	Pulse 4 duration (only 7-sec)	1	Second of
vp4	Pulse 4 voltage level (only 7-sec)	200	mV
				t4，1	Moment of sensor current reading 7 (only 7-sec)	4.625	sec
t4，4	Moment of sensor current reading 8 (only 7-sec)	5.00	sec
				t4，8	Moment of sensor current reading 9 (only 7-sec)	5.50	sec
tp5	Pulse 5 Start time (only 7-sec)	6	sec
				dp5	Pulse 5 duration (only 7-sec)	1	Second of
vp5	Pulse 5 voltage level (only 7-sec)	200	mV
				t5，1	Time of sensor current reading 10 (only 7-sec)	6.125	sec
t5，4	Time of sensor current reading 11 (only 7-sec)	6.50	sec
				t5，8	Time of sensor current reading 12 (only 7-sec)	7.00	sec

TABLE IV

Constant number	Description of the invention	Value of	Unit of
				R4min	Minimum limit of R4	0.45	--
R4max	Maximum limit of R4	0.85	--
				R5min	Minimum limit of R5	0.45	--
R5max	Maximum limit of R5	0.85	--
				Ratiomin	Ratio minimum limit	0.75	--
Ratiomax	Ratio maximum limit	1.25	--
				Glim	Glucose limits for different R4, R5 and R4/R5 values	50	mg/dL
R4Lmin	For less than GlimG of (A)25R4 minimum limit	0.45	--
				R4Lmax	For less than GlimG of (A)25R4 maximum limit	0.85	--
R5Lm，n	For less than GlimG of (A)25R5 minimum limit	0.45	--
				R5Lmax	For less than GlimG of (A)25R5 maximum limit	0.85	--
RatioLmin	For less than GlimG of (A)25Ratio minimum limit of	0.75	--
				RatioLmax	For less than GlimG of (A)25Ratio maximum limit of	1.25	--

Certain definitions are set forth below to provide a clearer and more consistent understanding of the specification and claims.

An "analyte" is defined as one or more substances present in a sample. The assay will determine the presence and/or concentration of the analyte present in the sample.

A "sample" is defined as a composition that may contain an unknown amount of analyte. Typically, the sample for electrochemical analysis is in liquid form, and preferably, the sample is an aqueous mixture. The sample may be a biological sample such as blood, urine or saliva. The sample may also be a derivative of a biological sample, such as an extract, a dilution, a filtrate or a reconstituted precipitate.

A "conductor" is defined as a conductive substance that remains stationary during an electrochemical analysis.

"accuracy" is defined as the closeness of the amount of analyte measured by the sensor system to the true amount of analyte in the sample. Accuracy can be expressed as a deviation of an analyte reading of the sensor system from a reference analyte reading. Larger deviation values reflect less accuracy.

"accuracy" is defined as the proximity of multiple analyte measurements to the same sample. Accuracy may be expressed as spread (spread) or variance between measurements.

A "redox reaction" is defined as a chemical reaction between two substances involving the transfer of at least one electron from a first substance to a second substance. Thus, redox reactions include oxidation and reduction. The oxidation half-cell reaction involves the loss of at least one electron from a first species, while the reduction half-cell reaction involves the addition of at least one electron from a second species. The ionic charge of the oxidized species increases by a value equal to the number of electrons lost. Also, the ionic charge reduction value of the reduced species is equal to the number of electrons obtained.

A "mediator" is defined as a substance that can be oxidized or reduced and that can transfer one or more electrons. Mediators are reagents in an electrochemical assay that are not target analytes, but rather provide indirect measurements of the analyte. In a simplified system, the mediator undergoes a redox reaction in response to oxidation or reduction of the analyte. The oxidized or reduced mediator then undergoes a relative reaction at the working electrode of the sensor strip, returning to its original oxidation number.

An "adhesive" is defined as a material that provides physical support to and holds a reagent while being chemically compatible with the reagent.

An "underfill condition" is defined as a sample of a biological fluid in a biosensor having a size or volume that is not large enough for the biosensor to accurately and/or precisely analyze the concentration of one or more analytes in the biological fluid.

A "handheld device" is defined as a device that can be held in a human hand and is portable. An example of a handheld device is available from Bayer HealthCare, LLC, Elkhart, INThe Elite blood glucose monitoring system is provided with a measuring device.

While various embodiments of the invention have been described, it will be apparent to those of ordinary skill in the art that other embodiments and implementations are possible within the scope of the invention.

Claims (51)

1. A method for detecting abnormal output in a biosensor, comprising:

normalizing an output signal from a redox reaction of an analyte in a sample of a biological fluid;

comparing the normalized output signal to at least one control limit; and

an error signal is generated when the normalized output signal is not within the at least one control limit.

2. The method of claim 1, further comprising generating an output signal in response to a redox reaction of an analyte in the sample of the biological fluid; and measuring the output signal prior to the step of normalizing the output signal.

3. The method of claim 1 or 2, wherein the step of normalizing an output signal from a redox reaction of an analyte in a sample of a biological fluid comprises determining a difference between at least one baseline output value and at least one measured output value of the output signal.

4. The method of claim 3, wherein the at least one baseline output value is a measured output value of the output signal.

5. A method as claimed in claim 1 or 2, wherein the output signal is responsive to a pulsed sequence.

6. The method of claim 1 or 2, wherein the step of normalizing the output signal from the redox reaction of the analyte in the sample of the biological fluid comprises dividing at least one output value in a pulse of the output signal by a first output value in the pulse of the output signal.

7. The method of claim 1 or 2, further comprising generating the output signal in response to a pulsed sequence.

8. The method of claim 7, wherein the output signal is responsive to a gated amperometric electrochemical system.

9. The method of claim 7, wherein the pulsed sequence comprises at least five pulses.

10. The method of claim 9, wherein the normalized current value R of the fourth pulse₄Represented by the formula:

wherein i_4，1Is a first current value, i, in said fourth pulse_4，8Is the last current value in the fourth pulse.

11. The method of claim 10, wherein R₄Greater than or equal to 0.45, and wherein R₄Less than or equal to 0.85.

12. The method of claim 9, wherein the normalized current value R of the fifth pulse₅Represented by the formula:

wherein i_5，1Is a first current value, i, in said fifth pulse_5，8Is the last current value in the fifth pulse.

13. The method of claim 12, wherein R₅Greater than or equal to 0.45, and wherein R₅Less than or equal to 0.85.

14. The method of claim 9, wherein a ratio of the normalized current value of the fourth pulse to the normalized current value of the fifth pulse is represented by:

wherein i_4，1Is a first current value, i, in said fourth pulse_4，8Is the last current value in the fourth pulse, i_5，1Is a first current value, i, in said fifth pulse_5，8Is the last current value in the fifth pulse.

15. The method of claim 14, wherein Ratio is greater than or equal to 0.75, and wherein Ratio is less than or equal to 1.25.

16. The method of claim 1 or 2, further comprising determining the at least one control limit from a statistical analysis of laboratory results.

17. The method of claim 1 or 2, further comprising applying an input signal to the sample of biological fluid.

18. The method of claim 17, wherein the input signal comprises a pulsed sequence.

19. The method of claim 18, wherein the input signal is responsive to a gated amperometric electrochemical system.

20. The method of claim 17, wherein the input signal comprises a polling input signal and a test input signal.

21. The method of claim 20, wherein the polling input signal has a polling pulse width of less than 300ms, and wherein the polling input signal has a polling pulse interval of less than 1 second.

22. The method of claim 21, wherein the polling input signal has a polling pulse width of 0.5ms to 75ms, and wherein the polling input signal has a polling pulse interval of 5ms to 300 ms.

23. The method of claim 20, wherein the test input signal has a test pulse width of less than 5 seconds, and wherein the test input signal has a test pulse interval of less than 15 seconds.

24. The method of claim 23, wherein the test input signal has a test pulse width of 0.1-3 seconds, and wherein the test input signal has a test pulse interval of 0.2-6 seconds.

25. The method of claim 20, further comprising:

applying the polling input signal in a polling period, wherein the polling period is less than 180 seconds; and

applying the test input signal in a test period, wherein the test period is less than 180 seconds.

26. The method of claim 25, further comprising:

applying the polling input signal in a polling period, wherein the polling period is 0.1-10 seconds; and

the test input signal is applied during a test period, wherein the test period is between 1 second and 100 seconds.

27. The method of claim 20, further comprising:

applying a polling input signal to the sample for 1.25 seconds, wherein the polling input signal has a polling pulse width of 5-10 ms and a polling pulse interval of 125 ms; and

a test input signal is applied to the sample for 7 seconds, wherein the test input signal has a test pulse width of 1 second and a test pulse interval of 1.5 seconds.

28. The method of claim 27, wherein the polling input signal has a potential of 400mV, wherein the test input signal has a first pulse with a potential of 400mV, wherein the test input signal has at least one other pulse with a potential of 200 mV.

29. The method of claim 20, further comprising applying the test input signal when a polling output signal is greater than or equal to a polling threshold.

30. The method of claim 29, wherein the polling threshold is 250 nA.

31. The method of claim 1 or 2, further comprising intermittently measuring the output signal.

32. The method of claim 31, further comprising measuring at least eight current values in at least one pulse of the output signal.

33. A biosensor for determining an analyte concentration in a biological fluid, comprising:

a sensor strip having a sample interface located on a substrate, wherein the sample interface is adjacent to a reservoir formed by the substrate;

a measurement device having a processor connected to a sensor interface, wherein the sensor interface is in electrical communication with the sample interface; and

wherein the processor normalizes an output signal from a redox reaction of an analyte in a sample of a biological fluid,

wherein the processor compares the normalized output signal to at least one control limit, an

Wherein the processor generates an error signal when the normalized output signal is not within the at least one control limit.

34. The biosensor of claim 33, where when the processor normalizes the output signal from a redox reaction of an analyte in a sample of a biological fluid, the processor divides at least one output value in a pulse of the output signal by a first output value in a pulse of the output signal.

35. The biosensor of claim 33 or 34, where the output signal is responsive to a pulsed sequence.

36. The biosensor of claim 35, where the output signal is responsive to a gated amperometry electrochemical system.

37. The biosensor of claim 33 or 34, where the output signal comprises at least five pulses.

38. The biosensor of claim 37, where the fourth pulseNormalized current value R₄Represented by the formula:

wherein i_4，1Is a first current value, i, in said fourth pulse_4，8Is the last current value in the fourth pulse.

39. The biosensor of claim 37, where the normalized current value of the fifth pulse, R₅Represented by the formula:

wherein i_5，1Is a first current value, i, in said fifth pulse_5，8Is the last current value in the fifth pulse.

40. The biosensor of claim 37, where a ratio of the normalized current value of the fourth pulse to the normalized current value of the fifth pulse is represented by:

wherein i_4，1Is a first current value, i, in said fourth pulse_4，8Is the last current value in the fourth pulse, i_5，1Is a first current value, i, in said fifth pulse_5，8Is the last current value in the fifth pulse.

41. The biosensor of claim 33 or 34, wherein the processor applies an input signal to the sample of biological fluid, wherein the input signal comprises a polling input signal and a test input signal.

42. The biosensor of claim 41, where the polling input signal has a polling pulse width of less than 300ms and a polling pulse interval of less than 1 second.

43. The biosensor of claim 41, where the test input signal has a test pulse width of less than 5 seconds, and where the test input signal has a test pulse interval of less than 15 seconds.

44. The biosensor of claim 41, where the processor applies the polling input signal in a polling period of less than 180 seconds, and where the processor applies the test input signal in a test period of less than 180 seconds.

45. The biosensor of claim 44, where the processor applies the polling input signal in a polling period of 0.1-10 seconds, and where the processor applies the test input signal in a test period of 1-100 seconds.

46. The biosensor in accordance with claim 41,

wherein the processor applies a polling input signal to the sample for 1.25 seconds, wherein the polling input signal has a polling pulse width of 5-10 ms, a polling pulse interval of 125ms, and a potential of 400 mV; and

wherein the processor applies a test input signal to the sample for 7 seconds, wherein the test input signal has a test pulse width of 1 second, a test pulse interval of 1.5 seconds, a first pulse at a potential of 400mV, and at least one other pulse at a potential of 200 mV.

47. The biosensor of claim 41, where the processor applies the test input signal when a polling output signal is greater than or equal to a polling threshold of 250 nA.

48. The biosensor of claim 33, where the processor determines a difference between at least one baseline output value and at least one measured output value of the output signal when the processor normalizes the output signal from a redox reaction of an analyte in a sample of the biological fluid.

49. The biosensor of any of claims 33, 34, 48, where the processor measures the output signal.

50. The biosensor of claim 49, where the processor measures the output signal intermittently.

51. The biosensor of any of claims 33, 34, 48, where the at least one control limit is predetermined from a statistical analysis of laboratory results.