Correcting calibration data used by diagnostic analyzers based on reagent storage conditions

Abstract

Calibration data initially provided with reagents to be used in diagnostic analyzers for measuring analytes in biological samples may need to be corrected based on reagent storage conditions including average storage temperature and storage time. By measuring pH and / or pO2 of a temperature correction fluid provided with the reagents, an average reagent storage temperature can be determined. The average reagent storage temperature along with a determined storage time of the reagents can be used to determine whether correction of the calibration data is needed and, if so, to correct that calibration data. Numerous other aspects are provided.

Description

CORRECTING CALIBRATION DATA USED BY DIAGNOSTIC ANALYZERS BASED ON REAGENT STORAGE CONDITIONS

[0001] This application claims benefit under 35 USC § 119(e) of U.S. Provisional Application No. 63 / 610,040, filed December 14, 2023. The entire contents of the above-referenced patent application are hereby expressly incorporated herein by reference. FIELD

[0002] This disclosure relates to calibration data used to calibrate diagnostic analyzers for measuring an analyte in a biological sample. BACKGROUND

[0003] A diagnostic analyzer may use one or more analyte / assay specific sensors and / or one or more testing reagents, which are a mixture of chemicals added to a biological sample (e.g., blood, urine, interstitial liquid, cerebrospinal liquid, and the like) or a non-biological buffered aqueous solution, to perform an “assay” (an analytic testing procedure) to determine an amount of an analyte that may be present in the sample. A “calibration reagent” is a solution with chemicals / substances added at specific target values that may be used by the diagnostic analyzer as a reference to check the validity of, and if necessary adjust, a measurement made by the diagnostic analyzer in order to maintain high analytical performance. Calibration reagents may be provided with related data that indicates, e.g., quantities, concentrations, or ratios of reagent components. However, storage conditions of the reagents before use in a diagnostic analyzer may affect those quantities, concentrations, or ratios, and thus the accuracy ofthe related data and subsequent assay calibration. This may, in turn, adversely affect the analytical performance of the assay.

[0004] Accordingly, improved apparatus and methods for calibrating diagnostic analyzer assays are desired. SUMMARY

[0005] In some embodiments, a method of calibrating an assay in a diagnostic analyzer for measuring an analyte in a biological sample is provided. The diagnostic analyzer includes a computer processor, and the method includes receiving a reagent cartridge in the diagnostic analyzer, wherein the reagent cartridge includes a temperature correction fluid, calibration data, and a date of manufacture. The method also includes determining, via the computer processor, a storage time of the reagent cartridge based on the date of manufacture; and measuring, via one or more analyte sensors of the diagnostic analyzer, pH or pO2(partial pressure of oxygen) of the temperature correction fluid. The method further includes determining, via the computer processor, an average storage temperature of the reagent cartridge based on measured pH or pO2relative to a respective pH or pO2value of the temperature correction fluid included in the calibration data; and correcting, via the computer processor, the calibration data in response to determined average storage temperature and determined storage time indicating that correction of the calibration data is needed. The method still further includes calibrating, via the computer processor, the diagnostic analyzer assay using corrected calibration data.

[0006] In some embodiments, a diagnostic analyzer for measuring an analyte in a biological sample is provided. The diagnostic analyzer includes a computer processor, an analyte sensor operative to measure the analyte in the biologicalsample or a quality control sample, one or more other analyte sensors operative to measure pH or pO2, a clock operative to indicate a current date, and a receptacle operative to receive a reagent cartridge. The reagent cartridge includes a temperature correction fluid, calibration data, and a date of manufacture. The computer processor is operative via programming instructions to receive the calibration data and the date of manufacture upon receipt of the reagent cartridge in the receptacle. The computer processor is also operative via programming instructions to determine a storage time of the reagent cartridge based on the date of manufacture and the current date provided by the clock, and measure pH or pO2of the temperature correction fluid via the one or more other analyte sensors. The computer processor is further operative via programming instructions to determine an average storage temperature based on measured pH or pO2relative to a respective pH or pO2value of the temperature correction fluid included in the calibration data. The computer processor is still further operative to correct the calibration data in response to the determined average storage temperature and the determined storage time indicating that correction of the calibration data is needed, and calibrate an assay of the diagnostic analyzer for measuring the analyte using corrected calibration data in response to the calibration data being corrected.

[0007] Still other aspects, features, and advantages of this disclosure may be readily apparent from the following detailed description and illustration of a number of example embodiments and implementations, including the best mode contemplated for carrying out the invention. This disclosure may also be capable of other and different embodiments, and its several details may be modified in various respects, all without departing from the scope of the invention. Forexample, although one embodiment described herein is with respect to calibrating assays for measuring creatinine and / or creatine in biological samples, this disclosure may be readily applicable to calibration of assays for measuring other analytes in biological samples such as, e.g., pCO2and glucose. The determination of average storage temperature as disclosed herein may be used to indicate that the reagent cartridge has been exposed to temperatures outside of a specified range. Advantageously, this may prevent usage of a reagent cartridge that may have been compromised because of exposure to such temperatures. Furthermore, this may prevent reporting of a patient test result that may be incorrect as a result of calibration data that is no longer valid. This disclosure is intended to cover all modifications, equivalents, and alternatives falling within the scope of the appended claims below. BRIEF DESCRIPTION OF DRAWINGS

[0008] The drawings described below are for illustrative purposes and are not necessarily drawn to scale. Accordingly, the drawings and descriptions are to be regarded as illustrative in nature, and not as restrictive. The drawings are not intended to limit the scope of the invention in any way.

[0009] FIG. 1 illustrates a schematic view of a diagnostic analyzer according to embodiments provided herein.

[0010] FIG. 2A illustrates a graph of pH stability versus storage time of a temperature correction fluid stored at 25º C according to embodiments provided herein.

[0011] FIG. 2B illustrates a graph of pO2stability versus storage time of a temperature correction fluid stored at 25º C according to embodiments provided herein.

[0012] FIG. 3 illustrates a graph of predicted creatine concentrations versus storage time at six average storage temperatures in a calibration solution having creatine and no creatinine at time of manufacture according to embodiments provided herein.

[0013] FIG. 4 illustrates a graph of predicted creatine concentrations and experimentally-determined creatine concentrations versus storage time at 25º C in a calibration solution having creatine and no creatinine at time of manufacture according to embodiments provided herein.

[0014] FIG. 5 illustrates a graph of predicted creatinine concentrations and experimentally-determined creatinine concentrations versus storage time at 25º C in a calibration solution having creatine and no creatinine at time of manufacture according to embodiments provided herein.

[0015] FIG. 6 illustrates a flowchart of a method of calibrating a diagnostic analyzer assay for measuring an analyte in a biological sample according to embodiments provided herein. DETAILED DESCRIPTION

[0016] Diagnostic analyzer assays are operative to measure an amount of an analyte (e.g., creatinine, glucose, serum albumin, oxygen, pH, sodium, potassium, etc.) that may be present in a biological sample (e.g., whole blood, serum, plasma, urine, interstitial liquid, pleural fluid, cerebrospinal liquid, and the like). To perform accurate analyte measurements, diagnostic analyzer assays may be calibrated by using calibration reagents and associated calibration data packaged with one or more testing reagents in a reagent cartridge or reagent kit (hereinafter referred to as a “reagent cartridge”). The reagent cartridge is configuredto be received in a diagnostic analyzer. A calibration reagent is a solution that includes chemicals / substances added at specific target values (e.g., levels, quantities, ratios, or concentrations) to a matrix (i.e., all components of a solution in addition to the analyte of interest) that provides a reference for the diagnostic analyzer. An analyte sensor (or like measurement device) contacting the calibration reagent generates an electrical signal that is measured (in, e.g., mV or nA) and converted into an amount of an analyte. In some embodiments, two or more calibration reagents with known (different) concentrations may be used. The values of the two or more electrical signals generated therefrom are used to create a calibration curve against which sensor measurements can be measured. Thereafter, upon the analyte sensor measuring an analyte in a quality control sample or a biological sample, the electrical signal generated thereby may be compared to the calibration reagents’ reference values (forming the calibration curve) to determine an amount of the analyte that may be present in the quality control sample or the biological sample.

[0017] The calibration data may be stored in an electronic device (e.g., a radio frequency identification (RFID) tag) provided with the reagent cartridge. The calibration data may alternatively be encoded in a barcode affixed to the reagent cartridge. The calibration data may include one or more reference values (e.g., the levels, quantities, ratios, or concentrations) of, e.g., one or more analytes to be measured and / or other chemicals / substances in one or more calibration reagents that are known at the time of manufacture. Upon receipt of the reagent cartridge in the diagnostic analyzer, the diagnostic analyzer may be calibrated using the calibration reagents and the calibration data.

[0018] However, storage conditions of the reagent cartridge prior to usage, such as, e.g., the length of time frommanufacture to installation in the diagnostic analyzer and / or the average temperature of the reagent cartridge while in storage, may cause one or more of the known component values in the calibration reagents to change. This may adversely affect the accuracy of the calibration and, thus, the measurement accuracy of the diagnostic analyzer.

[0019] In accordance with one or more embodiments provided herein, diagnostic analyzers may overcome the above-described disadvantages caused by reagent storage conditions by determining whether correction of the known component values in the calibration data is needed and, if so, by correcting those values. Determination of whether correction of the known component values in the calibration data is needed may be accomplished according to embodiments described herein by providing a temperature correction fluid in the reagent cartridge and including in the calibration data pH and / or pO2(partial pressure of oxygen) values initially measured in the temperature correction fluid at the time of manufacture. A temperature correction fluid has a predictable change in pH and / or pO2 from its initial manufacturing values in response to temperature over time. Also included in the calibration data is a date of manufacture of the reagent cartridge (indicating or representing a date of manufacture of the reagents and temperature correction fluid). Changes in the values of pH and / or pO2in the temperature correction fluid from the time of manufacture to the time of reagent cartridge installation in a diagnostic analyzer are used to determine (estimate) an average storage temperature (also known as a bulk kinetic temperature) of the reagent cartridge from time of manufacture to the time of installation. The average storage temperature and the storage time (measured from the date of manufacture to the date of reagent cartridge installation) are then used to determine whether correction ofthe calibration data is needed, and if so, the calibration data is corrected based on an experimentally-determined software model of how average storage temperature and storage time affect the relevant reagent calibration data.

[0020] More particularly, upon receipt of a reagent cartridge in a diagnostic analyzer and / or just prior to use in some embodiments, the diagnostic analyzer may determine the storage time of the reagent cartridge and measure pH and / or pO2in the temperature correction fluid. Based on the measured pH and / or pO2relative to the known pH and / or pO2values of the temperature correction fluid at the time of manufacture indicated in the calibration data, differences there between may be input to a first software model along with the storage time to determine (e.g., estimate / predict) an average storage temperature at which the reagent cartridge had been kept. Although measurement of only one of pH or pO2may be used to determine an average storage temperature, measurement of both pH and pO2may increase the confidence in the determined average storage temperature. Moreover, using pH and / or pO2to correct calibration data for pCO2and glucose in addition to creatinine would be advantageous.

[0021] Based on the determined average storage temperature and the storage time of the reagent cartridge, current levels / ratios / percentages of reagent components in a calibration reagent (or other solution included in the reagent cartridge) may be mathematically and / or experimentally determined via a second software model and compared with the original assigned values thereof included in the calibration data provided with the reagent cartridge. Differences between the originally-provided and the mathematically and / or experimentally-determined reagent component values exceeding, e.g., 0.1-1%, 1-2%, 3-5%, 6-8%, or 9-10% may indicate that correction of the calibration data is needed. The originalcalibration data may then be updated (i.e., replaced) with the mathematically and / or experimentally-determined new reagent component values and stored in the electronic device (e.g., RFID tag) of the reagent cartridge and / or a non-volatile memory of the diagnostic analyzer.

[0022] Assay calibration (or re-calibration) may then be performed using the corrected or updated calibration data. This calibration correction procedure may be repeated periodically while the reagent cartridge remains installed in the diagnostic analyzer to maintain accurate analyte measurements. If available in the diagnostic analyzer, a temperature sensor may provide the temperature input while the reagent cartridge is installed in the diagnostic analyzer.

[0023] Advantages of the apparatus and methods of calibrating analyte sensors according to embodiments described herein include maintaining high analyte measurement accuracy by correcting calibration data that may have been adversely affected by reagent storage conditions. Other advantages include indicating that the reagent cartridge had been stored outside of its specified range (e.g., 2º - 25º C), extending shelf-life and use-life of reagents used by the diagnostic analyzers, and / or expanding the temperature range at which reagents may be shipped and stored.

[0024] In accordance with one or more embodiments, diagnostic analyzers operative to correct calibration data based on reagent storage conditions will be explained in greater detail below in connection with FIGS. 1-6.

[0025] FIG. 1 illustrates a diagnostic analyzer 100 operative to measure one or more analytes that may be present in a biological sample according to one or more embodiments. Diagnostic analyzer 100 may include a controller 102, a sensor array 104, and a reagent cartridge receptacle 106. Diagnosticanalyzer 100 may include other components (not shown). Diagnostic analyzer 100 may, in some embodiments, be coupled to an automated track 108 for receiving and returning sample containers 110 carried by sample carriers 112. In some embodiments, diagnostic analyzer 100 may include a waste container for disposing sample containers 110 after testing. Each sample container 110 may contain a biological sample to be tested at diagnostic analyzer 100 for presence and quantity of one or more analytes (e.g., creatinine and / or creatine).

[0026] Controller 102 may include a computer processor 102P, a non-transitory memory 102M, and a clock 102C. Clock 102C may be operative to indicate the current date and time of day and be any suitable system or real-time clock. Non- transitory memory 102M may include programming instructions 102PI (e.g., software models, programs, algorithms, and the like) that may be executed by computer processor 102P. Programming instructions 102PI may additionally or alternatively be stored in another non-transitory computer readable medium. Non-transitory memory 102M may also include data / information that is accessible by computer processor 102P. While non-transitory memory 102M is shown internal to controller 102, all or a portion of non-transitory memory 102M may be external to and / or remote from controller 102.

[0027] Controller 102 may include a user interface (not shown), which may include a display, to enable a user to access a variety of control and status display screens and to enter commands and / or data into controller 102 related to the operation of the diagnostic analyzer 100. Controller 102 may alternatively or additionally include other processing devices / circuits (including microprocessors, A / D converters, amplifiers, filters, etc.), other storage devices, transceivers, interfaces, device drivers, and / or other electronics.

[0028] Controller 102 may be in communication with a system controller (not shown) of an automated diagnostic analysis system (also not shown), which may include multiple automated or semi-automated diagnostic analyzers of the same and / or different type as well as one or more input / output modules, centrifuges, quality check modules, decappers, aspirating / dispensing modules, heaters, storage and / or refrigeration modules, and / or other components.

[0029] In some embodiments, controller 102 may be in communication with other computers, other system controllers, or other devices of, e.g., an automated diagnostic analysis system, a laboratory information system, a medical facility, etc. The communication may occur either directly via wired and / or wireless connections or via a network for transmitting analysis measurement results thereto and / or for receiving biological sample related information including, e.g., one or more of patient information, time and date a sample was obtained, medical facility information, tracking and routing information, and / or any other information relevant to the biological samples to be analyzed. The network may be, e.g., a local area network (LAN), wide area network (WAN), or other suitable communication network, including wired and wireless networks. In some embodiments, controller 102 may be part of an automated diagnostic analysis system, a laboratory information system, a medical facility, etc.

[0030] Controller 102, via computer processor 102P executing programming instructions 102PI and, optionally, accessing data stored in non-transitory memory 102M, may be considered a special purpose machine particularly suited for controlling the overall operation of diagnostic analyzer 100, thus becoming an automated or semi-automated diagnostic analyzer 100. In particular, controller 102, via computer processor 102P executing programming instructions 102PI isoperative to, among other things, automatically calibrate the sensors of diagnostic analyzer 100, as described in more detail below.

[0031] Sensor array 104 may include a plurality of sensors operative to measure, via electrical signals, one or more analytes and / or other quantities. In some embodiments, sensor array 104 may include a sensor for measuring creatinine and / or creatine, a sensor for measuring pH, and / or a sensor for measuring pO2. Other types of sensors may additionally or alternatively be included. In some embodiments, sensor array 104 may be a replaceable unit or cartridge (similar to reagent cartridge 114) receivable in a sensor array receptacle (not shown) in diagnostic analyzer 100. In these embodiments, a sensor array cartridge may include its own electronic device (e.g., a radio frequency identification (RFID) tag) for storing corrected sensor calibration data.

[0032] Reagent cartridge receptacle 106 is configured to receive a reagent cartridge 114 therein. Reagent cartridge 114 may include an electronic device 114D operative to store data therein. In particular, electronic device 114D may have calibration data (e.g., reagent values) stored therein. In some embodiments, electronic device 114D may be or include, e.g., a radio frequency identification (RFID) tag. Electronic device 114D may be or include other types of data storage circuits and / or devices. In other embodiments, sensor calibration data may be encoded in a barcode (not shown) affixed to reagent cartridge 114. The barcode may be read by a barcode reader (not shown) of diagnostic analyzer 100 upon receipt of reagent cartridge 114 in reagent cartridge receptacle 106. Computer processor 102P may communicate wirelessly with reagent cartridge 114 (and more particularly with electronic device 114D) upon receipt of reagent cartridge 114 in reagent cartridge receptacle 106. Alternatively,reagent cartridge receptacle 106 may have electrical / electronic connectors / contacts for communicatively coupling computer processor 102P to electronic device 114D of reagent cartridge 114 via corresponding electrical / electronic connectors / contacts.

[0033] In some embodiments, diagnostic analyzer 100 may be configured and operative to measure creatinine and / or creatine in a biological sample. To do so, diagnostic analyzer 100 may use three enzymes (e.g., creatininase, creatinase, and sarcosine oxidase) to convert a creatinine analyte into a quantifiable electrical signal. In the electrode design of a creatinine sensor, an active electrode operative to consume creatinine contains all three enzymes, whereas an inactive electrode operative to consume creatine contains only two of the enzymes (creatinase and sarcosine oxidase).

[0034] A reagent cartridge 114 for embodiments of diagnostic analyzer 100 configured and operative to measure creatinine and / or creatine may include three calibration solutions: a first calibration solution of a first reagent with creatinine and creatine in a first ratio, a second calibration solution of a second reagent with creatine and no creatinine at time of manufacture, and a third calibration solution with no creatinine and no creatine (i.e., a measurand-free zero point). The three calibration solutions, when used together, may effectively calibrate out the creatine influence, enabling measurement system selectivity for creatinine to determine the amount of creatinine present in a quality control sample or biological sample.

[0035] Note, however, that creatinine and creatine in solution are known to reversibly interconvert (into each other) in a ratio of creatinine-to-creatine based on the pH of the solution they are dissolved in and the temperature of the solution. The interconversion of creatinine and creatine mayrender unreliable the quantified value of creatine in the second calibration solution determined at the time of manufacture and provided in the calibration data with the reagent cartridge. Accurate values of creatinine and creatine are needed to calibrate creatinine sensors with sufficient analytical performance. Without correction, such interconversion may reduce the shelf-life of such calibration reagents and / or may limit the temperature range at which such reagents can be stored.

[0036] In accordance with the embodiments described herein, the first calibration solution may contain a stable ratio of creatinine-to-creatine, and the second calibration solution may contain an unstable ratio of creatinine-to-creatine that may result in interconversion of creatinine to creatine (or vice versa) based on pH and temperature of the second calibration solution. That is, at a fixed temperature, creatine and creatinine will interconvert until equilibrium is achieved. As the solution gets closer to equilibrium, the speed of interconversion will slow. The levels (e.g., amounts, ratios, concentrations, etc.) of creatinine and creatine in each of the first and second calibration solutions at time of manufacture are encoded in electronic device 114D of reagent cartridge 114.

[0037] Possible changes in the levels of creatinine and creatine in the unstable second calibration solution at the time of sensor calibration may be estimated / predicted in accordance with the embodiments described herein by determining an average storage temperature and storage time of the reagent cartridge 114. Note that in accordance with the embodiments described herein the creatine and / or creatinine sensor and calibration solutions associated with creatine and creatinine are independent from the estimation of average storage temperature of the reagent cartridge. No directmeasurements of creatinine and / or creatine levels in the calibration solutions are used for estimation of the average storage temperature of the reagent cartridge. Using pH and / or pO2sensors and pH and / or pO2measurements from a temperature correction fluid allows the creatinine sensor and the calibration solutions being corrected to be independent.

[0038] Average storage temperature may be determined based on measurements and changes in pH and / or pO2in a temperature correction fluid also provided with reagent cartridge 114. The temperature correction fluid is preferably a separate solution from the first and second creatinine / creatine calibration solutions and the third creatinine / creatine-free calibration solution or is otherwise independent from the calibration of the analyte being corrected. The temperature correction fluid experiences the same temperature over the same period of time as the calibration reagents because they are contained within the same reagent cartridge. Based on pH and / or pO2changes in the temperature correction fluid, an average storage temperature can be determined and then applied to the first and second calibration solutions, which are calibrators for creatinine. Electronic device 114D may have encoded therein values of pH and pO2measured in the temperature correction fluid also provided with reagent cartridge 114. The temperature correction fluid is designed to have predictable pH and pO2changes over time and temperature.

[0039] In some embodiments, the calibration reagents and temperature correction fluid are buffered aqueous solutions with targeted values that may include sodium, potassium, ionized calcium, chloride, ionized magnesium, glucose, lactate, and urea tonometered with a mixture of gases including oxygen and carbon dioxide. To achieve and maintain a target value of oxygen and carbon dioxide, the reagents arefilled in a flexible laminate pouch that is heat-sealed with zero-headspace. The flexible laminate pouches of calibration reagents and temperature correction fluid with zero-headspace are then added to a reagent cartridge. The flexible laminate pouch may then include an access point (attached fitment) to connect to the reagent cartridge and then to the diagnostic analyzer. The reagent cartridge is a consumable to support the diagnostic analyzer. The reagent cartridge may also include the sensors, or the sensors may be a separate consumable, such as a sensor cartridge. The temperature correction fluid may be used for purposes other than shelf- life correction, such as, e.g., as a quality control solution.

[0040] A subsequent comparison of the values of pH and / or pO2measured in the temperature correction fluid at the time of manufacture with respective values of pH and / or pO2measured in the temperature correction fluid at the time of sensor calibration (e.g., at the time of installation of the reagent cartridge in the diagnostic analyzer or periodically thereafter) may be used to mathematically and / or experimentally determine via a software model an average storage temperature (also referred to as a bulk kinetic temperature] of the reagent cartridge 114. FIG. 2A illustrates pH decreasing in a temperature correction fluid maintained at 25º C over a period of time (e.g., 32 weeks), wherein line 202 represents actual pH data and line 204 represents modeled pH data. FIG. 2B illustrates pO2decreasing in a temperature correction fluid maintained at 25º C over a period of time (e.g., 32 weeks), wherein line 206 represents actual pO2data and line 208 represents modeled pO2data.

[0041] If using both pH and pO2, a weighted average is used (if they agree within, e.g., 10%). Confirmation that the shelf-life correction has been successful is confirmed by further assessment via quality control reagents. If thequality control assessment is determined to be out of acceptable limits, recalibrating the sensors and repeating the shelf-life correction process would be appropriate. Further failure to meet acceptable limits may be indicative of a quality issue for the overall system.

[0042] In addition to the determination of the average storage temperature, determination of the storage time of reagent cartridge 114 may be computed by computer processor 102P via the date of manufacture provided in electronic device 114D and the current date provided by clock 102C (FIG. 1) at the time the reagent cartridge 114 is installed in diagnostic analyzer 100.

[0043] The average storage temperature and the storage time may be applied as inputs to a mathematical and / or experimentally-determined software model to estimate / predict and, if needed, correct for creatinine and creatine levels in the unstable second calibration solution described above. The software model may be executed by computer processor 102P, may be stored in non-transitory memory 102M, and may be part of programming instructions 102PI (FIG. 1).

[0044] The software model may be based on the following equation: ^^ + ^^ ^ ି^^భା^మ^௧^^^^ ^ ଶ ^ ^^

[0045] wherein:

[0046] [A] is the molar concentration of creatinine at a given time in units of nM;

[0047] [A]0is the initial molar concentration of creatinine in units of nM;

[0048] k1is the kinetic constant of creatinine conversion to creatine in units of day-1;

[0049] k2is the kinetic constant of creatine conversion to creatinine in units of day-1; and

[0050] t is time in units of days.

[0051] Note that k1and k2are influenced by the average storage temperature and are determined via modeling experiments.

[0052] FIG. 3 illustrates a graph 300 representing the second calibration solution (having creatine and no creatinine at time of manufacture) and shows estimated / predicted outputs of the software model for creatine concentrations (in units of mM) over a 300-day storage time for six average storage temperatures according to one or more embodiments. Creatine concentration curve 304 represents estimated / predicted creatine concentrations at an average storage temperature of 4º C. Creatine concentration curve 320 represents estimated / predicted creatine concentrations at an average storage temperature of 20º C. Creatine concentration curve 325 represents estimated / predicted creatine concentrations at an average storage temperature of 25º C. Creatine concentration curve 330 represents estimated / predicted creatine concentrations at an average storage temperature of 30º C. Creatine concentration curve 332 represents estimated / predicted creatine concentrations at an average storage temperature of 32º C. And creatine concentration curve 337 represents estimated / predicted creatine concentrations at an average storage temperature of 37º C.

[0053] FIG. 4 illustrates a graph 400 representing the second calibration solution (having creatine and no creatinine at time of manufacture) and shows a comparison of estimated / predicted creatine concentrations andexperimentally-determined creatine concentrations versus a 100-day storage time at 25º C according to one or more embodiments. As shown, the estimated / predicted creatine concentrations closely track the experimentally-determined creatine concentrations, thus establishing the validity of the software model.

[0054] FIG. 5 illustrates a graph 500 also representing the second calibration solution (having creatine and no creatinine at time of manufacture) and shows a comparison of estimated / predicted creatinine concentrations and experimentally-determined creatinine concentrations versus an 80-day storage time at 25º C according to one or more embodiments. As shown, creatinine increases over time (as creatine in the solution decreases over time – see FIG. 4). As also shown, the estimated / predicted creatinine concentrations closely track the experimentally-determined creatinine concentrations, thus again establishing the validity of the software model.

[0055] FIG. 6 illustrates a method 600 of calibrating a diagnostic analyzer assay for measuring an analyte in a biological sample, wherein the diagnostic analyzer includes a computer processor, according to one or more embodiments. At process block 602, method 600 may include receiving a reagent cartridge in the diagnostic analyzer, the reagent cartridge including a temperature correction fluid, calibration data, and a date of manufacture. For example, referring to FIG. 1, reagent cartridge 114 may be received in diagnostic analyzer 100 at reagent cartridge receptacle 106. Reagent cartridge 114 may include electronic device 114D that may have stored therein calibration data, such as, e.g., pH and pO2values of a temperature correction fluid included with the reagent cartridge. Electronic device 114D may also have stored therein a date of manufacture of the reagent cartridge 114.

[0056] At process block 604, method 600 may include determining, via the computer processor, a storage time of the reagent cartridge based on the date of manufacture. For example, computer processor 102P may receive a date of manufacture from electronic device 114D and a date of installation of reagent cartridge 114 from clock 102C upon installation of reagent cartridge 114 in diagnostic analyzer 100. Computer processor 102P may then determine a number of days (storage time) between the date of manufacture and the date of installation.

[0057] At process block 606, method 600 may include measuring, via one or more analyte sensors of the diagnostic analyzer, pH and / or pO2of the temperature correction fluid included with the reagent cartridge.

[0058] At process block 608, method 600 may include determining, via the computer processor, an average storage temperature of the reagent cartridge based on the measured pH and / or pO2relative to respective pH and / or pO2values included in the calibration data. For example, a first software model executing on computer processor 102P may determine an average storage temperature at which the reagent cartridge had been kept based on measured changes in pH and / or pO2values and the determined storage time. The first software model may be stored in non-transitory memory 102M.

[0059] Method 600 may include at process block 610 correcting, via the computer processor, the calibration data in response to the determined average storage temperature and the determined storage time indicating that correction of the calibration data is needed. For example, the determined average storage temperature and the determined storage time may be input to a second software model executing on computer processor 102P. The second software model, which may be stored in non-transitory memory 102M determines how averagestorage temperature and storage time affect reagent calibration data, and if the reagent calibration data has changed by more than a predetermined amount or percentage, computer processor 102P may correct the reagent calibration data.

[0060] And method 600 may include at process block 612 calibrating the analyte sensor using corrected calibration data.

[0061] While this disclosure is susceptible to various modifications and alternative forms, specific method and apparatus embodiments have been shown by way of example in the drawings and are described in detail herein. It should be understood, however, that the particular methods and apparatus disclosed herein are not intended to limit the disclosure or the following claims.

[0062] Independent of the grammatical term usage, individuals with male, female or other gender identities are included within the term.

[0063] ILLUSTRATIVE EMBODIMENTS

[0064] The following provides a non-limiting list of illustrative embodiments of this disclosure:

[0065] Example Embodiment 1: A method of calibrating an assay in a diagnostic analyzer for measuring an analyte in a biological sample, the diagnostic analyzer including a computer processor, the method comprising:

[0066] receiving a reagent cartridge in the diagnostic analyzer, the reagent cartridge including a temperature correction fluid, calibration data, and a date of manufacture;

[0067] determining, via the computer processor, a storage time of the reagent cartridge based on the date of manufacture;

[0068] measuring, via one or more analyte sensors of the diagnostic analyzer, pH or pO2of the temperature correction fluid;

[0069] determining, via the computer processor, an average storage temperature of the reagent cartridge based on the measured pH or pO2relative to a respective pH or pO2value of the temperature correction fluid included in the calibration data;

[0070] correcting, via the computer processor, the calibration data in response to the determined average storage temperature and the determined storage time indicating that correction of the calibration data is needed; and

[0071] calibrating, via the computer processor, the diagnostic analyzer assay using corrected calibration data.

[0072] Example Embodiment 2: The method of Example Embodiment 1, wherein:

[0073] the measuring further comprises measuring, via the one or more analyte sensors of the diagnostic analyzer, pH and pO2of the temperature correction fluid; and

[0074] the determining, via the computer processor, the average storage temperature further comprises determining, via the computer processor, the average storage temperature of the reagent cartridge based on the measured pH and pO2relative to respective pH and pO2values of the temperature correction fluid included in the calibration data.

[0075] Example Embodiment 3: The method of any one of the previous Example Embodiments, wherein the determining, via the computer processor, the average storage temperature of the reagent cartridge comprises determining a difference between the measured pH or pO2and the respective pH or pO2value of the temperature correction fluid included in the calibration data, and providing the difference to a software modeloperative to determine the average storage temperature, the software model executed by the computer processor.

[0076] Example Embodiment 4: The method of any one of the previous Example Embodiments, further comprising, prior to the determining via the computer processor the average storage temperature, determining experimentally a change in pH in the temperature correction fluid over a range of temperatures and time periods.

[0077] Example Embodiment 5: The method of any one of the previous Example Embodiments, further comprising, prior to the determining via the computer processor the average storage temperature, determining experimentally a change in pO2in the temperature correction fluid over a range of temperatures and time periods.

[0078] Example Embodiment 6: The method of any one of the previous Example Embodiments, wherein the reagent cartridge includes an electronic device storing the calibration data and the date of manufacture, and the method further comprises receiving, via the computer processor, the calibration data and the date of manufacture stored in the electronic device in response to the receiving the reagent cartridge in the diagnostic analyzer.

[0079] Example Embodiment 7: The method of any one of the previous Example Embodiments, wherein the electronic device comprises a radio frequency identification (RFID) tag.

[0080] Example Embodiment 8: The method of any one of the previous Example Embodiments, wherein the determining, via the computer processor, the storage time of the reagent cartridge comprises:

[0081] receiving, via the computer processor, the date of manufacture from the reagent cartridge; and

[0082] determining, via the computer processor, a difference in days between the date of manufacture and a date the reagent cartridge was received in the diagnostic analyzer as indicated by a clock of the diagnostic analyzer.

[0083] Example Embodiment 9: The method of any one of the previous Example Embodiments, wherein the reagent cartridge includes multi-analyte reagents.

[0084] Example Embodiment 10: The method of any one of the previous Example Embodiments, wherein:

[0085] the calibration data includes levels of creatinine and creatine in each of two calibration reagents included in the reagent cartridge as of the date of manufacture;

[0086] the determined average storage temperature and the determined storage time are used to determine current levels of creatinine and creatine in the two calibration reagents; and

[0087] the computer processor stores determined current levels of creatinine and creatine in the calibration data in the reagent cartridge if different than the levels of creatinine and creatine as of the date of manufacture.

[0088] Example Embodiment 11: The method of any one of the previous Example Embodiments, wherein the diagnostic analyzer comprises an analyte sensor operative to measure an amount of creatinine or creatine present in the biological sample.

[0089] Example Embodiment 12: The method of any one of the previous Example Embodiments, wherein the biological sample comprises whole blood, serum, plasma, urine, interstitial liquid, pleural fluid, or cerebrospinal liquid.

[0090] Example Embodiment 13: A diagnostic analyzer for measuring an analyte in a biological sample, comprising:

[0091] a computer processor;

[0092] an analyte sensor operative to measure the analyte in the biological sample or a quality control sample;

[0093] a receptacle operative to receive a reagent cartridge, the reagent cartridge including a temperature correction fluid, calibration data, and a date of manufacture;

[0094] one or more other analyte sensors operative to measure pH or pO2; and

[0095] a clock operative to indicate a current date; wherein:

[0096] the computer processor is operative via programming instructions to:

[0097] receive the calibration data and the date of manufacture upon receipt of the reagent cartridge in the receptacle;

[0098] determine a storage time of the reagent cartridge based on the date of manufacture and the current date provided by the clock;

[0099] measure via the one or more other analyte sensors pH or pO2of the temperature correction fluid;

[0100] determine an average storage temperature based on the measured pH or pO2relative to a respective pH or pO2value of the temperature correction fluid included in the calibration data;

[0101] correct the calibration data in response to the determined average storage temperature and the determined storage time indicating that correction of the calibration data is needed; and

[0102] calibrate an assay of the diagnostic analyzer for measuring the analyte using corrected calibration data in response to the calibration data being corrected.

[0103] Example Embodiment 14: The diagnostic analyzer of Example Embodiment 13, wherein the computer processor is further operative via programming instructions to:

[0104] measure via the one or more other analyte sensors pH and pO2 of the temperature correction fluid; and

[0105] determine an average storage temperature based on the measured pH and pO2 relative to respective pH and pO2 values of the temperature correction fluid included in the calibration data.

[0106] Example Embodiment 15: The diagnostic analyzer of Example Embodiment 13 or 14, further comprising the reagent cartridge received in the receptacle.

[0107] Example Embodiment 16: The diagnostic analyzer of any one of Example Embodiments 13-15, wherein the temperature correction fluid comprises predictable changes in pH over a range of temperatures and time periods.

[0108] Example Embodiment 17: The diagnostic analyzer of any one of Example Embodiments 13-16, wherein the temperature correction fluid comprises predictable changes in pO2over a range of temperatures and time periods.

[0109] Example Embodiment 18: The diagnostic analyzer of any one of Example Embodiments 13-17, wherein the reagent cartridge further comprises one or more testing reagents and one or more calibration reagents.

[0110] Example Embodiment 19: The diagnostic analyzer of any one of Example Embodiments 13-18, wherein the calibration data and the date of manufacture are stored in an electronicdevice included with the reagent cartridge or are encoded in a barcode included with the reagent cartridge.

[0111] Example Embodiment 20: The diagnostic analyzer of any one of Example Embodiments 13-19, wherein the computer processor is further operative via programming instructions to store the corrected calibration data in the electronic device.

Claims

CLAIMS What is claimed is:

1. A method of calibrating an assay in a diagnostic analyzer for measuring an analyte in a biological sample, the diagnostic analyzer including a computer processor, the method comprising: receiving a reagent cartridge in the diagnostic analyzer, the reagent cartridge including a temperature correction fluid, calibration data, and a date of manufacture; determining, via the computer processor, a storage time of the reagent cartridge based on the date of manufacture; measuring, via one or more analyte sensors of the diagnostic analyzer, pH or pO2of the temperature correction fluid; determining, via the computer processor, an average storage temperature of the reagent cartridge based on measured pH or pO2relative to a respective pH or pO2value of the temperature correction fluid included in the calibration data; correcting, via the computer processor, the calibration data in response to determined average storage temperature and determined storage time indicating that correction of the calibration data is needed; and calibrating, via the computer processor, the diagnostic analyzer assay using corrected calibration data.

2. The method of claim 1, wherein: the measuring further comprises measuring, via the one or more analyte sensors of the diagnostic analyzer, pH and pO2of the temperature correction fluid; and the determining, via the computer processor, the average storage temperature further comprises determining, via the computer processor, the average storage temperature of thereagent cartridge based on the measured pH and pO2relative to respective pH and pO2values of the temperature correction fluid included in the calibration data.

3. The method of claim 1, wherein the determining, via the computer processor, the average storage temperature of the reagent cartridge comprises determining a difference between the measured pH or pO2and the respective pH or pO2value of the temperature correction fluid included in the calibration data, and providing the difference to a software model operative to determine the average storage temperature, the software model executed by the computer processor.

4. The method of claim 1, further comprising, prior to the determining via the computer processor the average storage temperature, determining experimentally a change in pH in the temperature correction fluid over a range of temperatures and time periods.

5. The method of claim 1, further comprising, prior to the determining via the computer processor the average storage temperature, determining experimentally a change in pO2in the temperature correction fluid over a range of temperatures and time periods.

6. The method of claim 1, wherein the reagent cartridge includes an electronic device storing the calibration data and the date of manufacture, and the method further comprises receiving, via the computer processor, the calibration data and the date of manufacture stored in the electronic device in response to the receiving the reagent cartridge in the diagnostic analyzer.

7. The method of claim 6, wherein the electronic device comprises a radio frequency identification (RFID) tag.

8. The method of claim 1, wherein the determining, via the computer processor, the storage time of the reagent cartridge comprises: receiving, via the computer processor, the date of manufacture from the reagent cartridge; and determining, via the computer processor, a difference in days between the date of manufacture and a date the reagent cartridge was received in the diagnostic analyzer as indicated by a clock of the diagnostic analyzer.

9. The method of claim 1, wherein the reagent cartridge includes multi-analyte reagents.

10. The method of claim 1, wherein: the calibration data includes levels of creatinine and creatine in each of two calibration reagents included in the reagent cartridge as of the date of manufacture; the determined average storage temperature and the determined storage time are used to determine current levels of creatinine and creatine in the two calibration reagents; and the computer processor stores determined current levels of creatinine and creatine in the calibration data in the reagent cartridge if different than the levels of creatinine and creatine as of the date of manufacture.

11. The method of claim 10, wherein the diagnostic analyzer comprises an analyte sensor operative to measure an amount of creatinine or creatine present in the biological sample.

12. The method of claim 1, wherein the biological sample comprises whole blood, serum, plasma, urine, interstitial liquid, pleural fluid, or cerebrospinal liquid.

13. A diagnostic analyzer for measuring an analyte in a biological sample, comprising: a computer processor; an analyte sensor operative to measure the analyte in the biological sample or a quality control sample; a receptacle operative to receive a reagent cartridge, the reagent cartridge including a temperature correction fluid, calibration data, and a date of manufacture; one or more other analyte sensors operative to measure pH or pO2; and a clock operative to indicate a current date; wherein: the computer processor is operative via programming instructions to: receive the calibration data and the date of manufacture upon receipt of the reagent cartridge in the receptacle; determine a storage time of the reagent cartridge based on the date of manufacture and the current date provided by the clock; measure, via the one or more other analyte sensors, pH or pO2of the temperature correction fluid; determine an average storage temperature based on measured pH or pO2relative to a respective pH or pO2value of the temperature correction fluid included in the calibration data; correct the calibration data in response to the determined average storage temperature and the determined storage time indicating that correction of the calibration data is needed; andcalibrate an assay of the diagnostic analyzer for measuring the analyte using corrected calibration data in response to the calibration data being corrected.

14. The diagnostic analyzer of claim 13, wherein the computer processor is further operative via programming instructions to: measure, via the one or more other analyte sensors, pH and pO2of the temperature correction fluid; and determine an average storage temperature based on the measured pH and pO2relative to respective pH and pO2values of the temperature correction fluid included in the calibration data.

15. The diagnostic analyzer of claim 13, further comprising the reagent cartridge received in the receptacle.

16. The diagnostic analyzer of claim 15, wherein the temperature correction fluid comprises predictable changes in pH over a range of temperatures and time periods.

17. The diagnostic analyzer of claim 15, wherein the temperature correction fluid comprises predictable changes in pO2over a range of temperatures and time periods.

18. The diagnostic analyzer of claim 15, wherein the reagent cartridge further comprises one or more testing reagents and one or more calibration reagents.

19. The diagnostic analyzer of claim 15, wherein the calibration data and the date of manufacture are stored in an electronic device included with the reagent cartridge or are encoded in a barcode included with the reagent cartridge.

20. The diagnostic analyzer of claim 19, wherein the computer processor is further operative via programming instructions to store the corrected calibration data in the electronic device.

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