Control Loop-Based Value Adjustment in an In Vitro Diagnostic System

Abstract

To enable provision of a consistent result value by an in-vitro diagnosis device.SOLUTION: The present invention relates to: a system comprising an in-vitro diagnosis device, and at least one control unit bidirectionally connected to the in-vitro diagnosis device and configured to evaluate a deviation of an internal calibration / control measurement parameter from a defined standard value of at least one in-vitro diagnosis device, the control unit being configured to modify the standard value, for which a deviating internal calibration / control measurement parameter has been detected, and to transmit the modified standard value to the in-vitro diagnosis device; and a corresponding method.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a system that enables an in vitro diagnostic device to supply consistent result values, including an in vitro diagnostic device and at least one control unit that is bidirectionally connected to the in vitro diagnostic device and is configured to evaluate deviations of internal calibration / control measurement parameters from a defined reference value of at least one in vitro diagnostic device. The control unit is configured to correct the reference value against which a deviated internal calibration / control measurement parameter is detected and transmit the corrected reference value to the in vitro diagnostic device; and to a corresponding method.

Background Art

[0002] In vitro diagnostic (IVD) systems measure qualitative and quantitative results of multiple parameters of a health state using patient samples. Patient samples are typically fluids such as blood, serum, plasma, or urine. Each parameter is generally based on a specific biochemical test capable of reacting with the patient sample, and thus the results can be measured by an IVD analysis device. Such highly automated analysis devices can process patient samples and parameterize specific assays with their reagent components to obtain patient results. The patient results are then typically communicated to healthcare providers and can indicate whether the patient's health state is normal or abnormal. In the case of quantitative tests, a range is generally established for classifying the state within or outside the target value range. Therefore, it is very important that the in vitro diagnostic system can reproduce results in a low-variation state. If the spread of the results becomes too large, the diagnosis becomes complicated and it becomes difficult or impossible to associate measurement results with each other over time.

[0003] To faithfully and accurately reflect the patient's condition with respect to the parameter of interest, in order to reduce the variability of the measurement results and ensure the accuracy and precision of the measurement results, reagent batches typically have target values specifically assigned to the batch, which values are taken into account when performing the test and are corrected after changing the batch. However, the fact that the target values vary is contrary to the concept of established medical decision points for explaining the conditions related to diagnosis.

[0004] Furthermore, each assay typically has a control system, i.e., a standardized reference substance is tested daily or weekly before the actual patient samples can be tested. A value is assigned to the reference substance, and that value must be within a specific range to confirm the functional ability of the in vitro diagnostic system. The variation of those ranges can be up to 20%, so the variation of the results becomes very large. If the value of the reference substance of an individual system is outside the aforementioned range, system-specific values that can define the characteristics of the individual system may be required.

[0005] The aforementioned means for reducing the variability of the measurement results indicate that previous procedures may lead to inaccuracies in the measurement of patient samples and delays in diagnosis.

Summary of the Invention

Problems to be Solved by the Invention

[0006] Therefore, an object of the present invention is to provide a method and means for more accurately performing an in vitro diagnostic method and ensuring a consistent supply of result values.

Means for Solving the Problems

[0007] That object is achieved by the subject matter of the independent claims. The dependent claims reflect further advantageous aspects of the present invention.

[0008] The present invention first provides a system comprising: - At least one in vitro diagnostic device configured to perform a diagnostic assay, the in vitro diagnostic device being configured to detect a deviation of an internal calibration / control measurement parameter from a specified reference value or calibration curve and send it to a control unit; - At least one control unit bi-directionally connected to the at least one in vitro diagnostic device and configured to evaluate a deviation of an internal calibration / control measurement parameter from a specified reference value of the at least one in vitro diagnostic device, the control unit further accessing data from a database for evaluation; comprising; To enable the in vitro diagnostic device to supply consistent result values, the control unit is configured to correct the reference value against which a deviated internal calibration / control measurement parameter was detected and send the corrected reference value to the in vitro diagnostic device that detected the deviation. Regarding the system.

[0009] The system advantageously performs adjustment-based value adjustment, thereby improving the accuracy of measurement results and enabling the supply of consistent result values over the long term, independent of batches and influences.

[0010] In a preferred embodiment, the internal calibration / control measurement parameter is a parameter related to the assay reagent used to perform the in vitro diagnosis.

[0011] In another preferred embodiment, the internal calibration / control measurement parameter is a device system component parameter.

[0012] In another preferred embodiment of the system according to the invention, the control unit is configured to evaluate a deviation from a specified reference value depending on the assay reagent batch used, the device system component, or the device type.

[0013] In another preferred embodiment of the system according to the invention, at least one in vitro diagnostic device is further configured to send measurement data of a patient sample measured in an assay (patient assay) to a control unit.

[0014] More preferably, the control unit is further configured to evaluate the measurement data of the patient assay using prior measurement data, controls, and / or calibrations of the patient assay.

[0015] In another preferred embodiment of the present system, the evaluation includes a comparison of deviations from internal calibration / control measurement parameters and, optionally, a comparison of measurement data of patient assays of a number of in vitro diagnostic devices.

[0016] In another preferred embodiment of the system according to the invention, the control unit is configured to access a database containing data on measurement or calibration / control measurement parameters associated with assay reagents and / or data on device system component parameters and / or data on patient assays.

[0017] The reference value is preferably corrected by a correction factor determined based on (i) the individual deviation of the in vitro diagnostic device from the reference value, (ii) the assay reagent batch-dependent deviation of a plurality of in vitro diagnostic devices from the reference value, (iii) the deviation of the measurement data of the patient assay from the prior measurement data of the patient assay, (iv) the device type-dependent deviation of a plurality of in vitro diagnostic devices from the reference value, (v) the device system component-dependent deviation of a plurality of in vitro diagnostic devices from the reference value, (vi) the deviation of the measurement or calibration / control measurement parameters from the measurement or calibration / control measurement parameters in a number of in vitro diagnostic devices, and / or (vii) a combination of the device system component-dependent deviation, the assay reagent batch-dependent deviation, and / or the deviation from the measurement data of the patient assay.

[0018] In an additional preferred embodiment, the present application relates to a system as described above, wherein at least one in vitro diagnostic device is configured to detect a deviation of an internal calibration / control measurement parameter from a defined reference value once a year, or once during the useful life, or a portion thereof, of the in vitro diagnostic device, assay reagent, or system component, and send it to a control unit.

[0019] In another aspect, the present application is a method for modifying a defined reference value of an internal calibration / control measurement parameter of at least one in vitro diagnostic device, wherein the internal calibration / control measurement parameter measured in the in vitro diagnostic device has a deviation from the reference value, and the method includes sending the deviation to at least one control unit, evaluating the deviation in the control unit, and sending a modified reference value based on the deviation to the in vitro diagnostic device that detected the deviation. Optionally, measurement data of a patient assay is further sent to the control unit. Preferably, the deviation from the initial measurement of the internal calibration / control measurement parameter, more preferably the deviation of the internal calibration / control measurement parameter from the defined reference value, is detected and sent once a year, or once during the useful life, or a portion thereof, of the in vitro diagnostic device, assay reagent, or system component.

[0020] In another preferred embodiment of the method according to the present invention, the internal calibration / control measurement parameter is a parameter related to an assay reagent used to perform an in vitro diagnosis or a device system component parameter.

[0021] In an additional preferred embodiment, the evaluation of the deviation from the defined reference value is performed according to the assay reagent batch used, device system component, and / or device type.

[0022] In another preferred embodiment of the method according to the invention, the evaluation comprises a comparison of the deviations of the internal calibration / control measurement parameters of a number of in vitro diagnostic devices.

[0023] In a further preferred embodiment of the method according to the invention, the reference value is (i) the individual deviation of an in vitro diagnostic device from the reference value, (ii) the assay reagent batch-dependent deviation of a plurality of in vitro diagnostic devices from the reference value, (iii) the deviation of the measurement data of a patient assay from the preceding measurement data of the patient assay, (iv) the device type-dependent deviation of a plurality of in vitro diagnostic devices from the reference value, (v) the device system component-dependent deviation of a plurality of in vitro diagnostic devices from the reference value, (vi) the deviation of a measurement or calibration / control measurement parameter from a measurement or calibration / control measurement parameter in a number of in vitro diagnostic devices, and / or (vii) a combination of device system component-dependent deviation, assay reagent batch-dependent deviation, and / or deviation from the measurement data of a patient assay, corrected by a correction factor determined on the basis thereof.

Brief Description of the Drawings

[0024]

Figure 1

Figure 2

Figure 3

Embodiments for Carrying Out the Invention

[0025] The present invention has been described with respect to specific embodiments, but the description should not be construed in a limiting sense.

[0026] Before explaining exemplary embodiments of the present invention in detail, important definitions are given to understand the present invention.

[0027] Unless the context clearly dictates otherwise, as used in this specification and the appended claims, the singular forms "a" and "an" also include their respective plural forms.

[0028] Regarding the present invention, the terms "approximately" and "about" represent the range of accuracy that those skilled in the art understand still ensures the technical effect of the structure in question. Typically, the term indicates a deviation of ±20%, preferably ±15%, more preferably ±10%, and even more preferably ±5% from the indicated numerical value.

[0029] It should be understood that the term "comprising" is not limiting. In the present invention, the terms "consisting of" or "essentially consisting of" are considered preferred specific expressions of the term "comprising of".

[0030] When a group is defined herein below to include at least a certain number of embodiments, this means that it preferably also includes a group consisting of only those embodiments.

[0031] Furthermore, in the specification or claims, "(i)", "(ii)", "(iii)", or "(a)", "(b)", "(c)", "(d)", or "first", "second", "third", etc. and similar terms are used to distinguish similar elements and do not necessarily describe a sequential or chronological order.

[0032] It should be understood that the terms used in this way are interchangeable under appropriate circumstances and that the embodiments of the present invention described herein can be used in an order different from the order described herein. When those terms relate to techniques, methods, or steps of use, there is no time coherence or time interval coherence between the steps, that is, unless otherwise specified, the steps can be executed simultaneously or there can be a time interval such as seconds, minutes, hours, days, weeks, etc. between those steps.

[0033] It should be understood that the present invention is not limited to the specific methods, protocols, etc. described herein, as they may vary. It should also be understood that the terms used herein are for the purpose of merely describing particular embodiments and do not limit the scope of the present invention, which is limited only by the appended claims.

[0034] The drawings should be interpreted as being schematic representations, and the elements shown in the drawings are not necessarily shown to scale. Rather, the various elements are represented so that their function and general purpose will be apparent to those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0035] As mentioned above, the present invention relates to a system comprising: at least one in vitro diagnostic device configured to perform a diagnostic assay, the in vitro diagnostic device being configured to detect a deviation of an internal calibration / control measurement parameter from a defined reference value or calibration curve and send it to a control unit; and at least one control unit bi-directionally connected to the at least one in vitro diagnostic device and configured to evaluate a deviation of an internal calibration / control measurement parameter from a defined reference value of the at least one in vitro diagnostic device, the control unit further accessing data from a database for the evaluation. In order to enable the in vitro diagnostic device to supply consistent result values, the control unit is configured to correct the reference value against which the deviated internal calibration / control measurement parameter was detected and send the corrected reference value to the in vitro diagnostic device that detected the deviation.

[0036] The term "calibration / control measurement parameter" is used herein with respect to calibration and / or control measurement parameters in this instance.

[0037] As used herein, the term "in vitro diagnostic device" refers to a device configured to be able to perform a diagnostic assay or determine the result of a diagnostic assay on a sample, preferably a biological sample, preferably either fully automatically or semi-automatically. In vitro diagnostic devices can have various forms and functions, for example, be configured as a stand-alone device or operate in the form of an integrated in vitro diagnostic large-scale device or in cooperation with a further device. In vitro diagnostic devices are typically configured to perform various diagnostic tests or assays. To perform different tests, corresponding reagents, controls, standards, and test protocols are adopted, which may vary depending on the form of the assay, the scope of the assay, and the purpose of the assay.

[0038] In the context of the present invention, "sample" is intended to mean a material (specimen) that is considered to contain the substance to be detected. The term "sample" specifically includes biological fluids of humans or animals, such as blood, plasma, serum, sputum, exudate, bronchoalveolar fluid, lymph, synovial fluid, semen, vaginal mucus, feces, urine, body fluids, or alternatively, tissue samples or cell culture samples prepared accordingly, for example, by homogenization or cell lysis, for optical analysis determination, preferably nephelometric analysis determination. Furthermore, for example, vegetable fluids or tissues, forensic samples, water samples, and wastewater samples, food materials, and pharmaceuticals that are intended to receive preparation of the corresponding sample prior to determination in some cases can also be used as samples.

[0039] Performing a diagnostic assay preferably involves measuring the concentration and / or activity of one or more analytes in a sample by quantitative detection and / or qualitative detection. The term "quantitative detection" includes semi-quantitative methods that merely record the approximate amount, concentration, or activity of an analyte in a sample or can only be used with respect to a specified value of relative amount, concentration, or activity. Qualitative detection is intended to mean detecting the actual presence of an analyte in a sample or a specified value that the amount, concentration, or activity of an analyte in the sample is below or above a particular single threshold or particular multiple thresholds.

[0040] Each assay, in this case, typically has its own control system, i.e., a standardized reference substance / calibrant, which is tested at regular time intervals, e.g., daily or weekly, before it becomes possible to examine actual patient samples.

[0041] Reagents used in in vitro assays are usually batch-produced and must meet predetermined set values such as concentration, activity, etc. Furthermore, specifically determined values assigned specifically to a batch can be assigned to the reagents, and those values may vary by batch and must be taken into account when performing the assay. Such batch-specific values are typically indicated in the product manual attached with the product packaging and can be read or used for performing the assay when executing the assay. After being input into an in vitro diagnostic device, those values are taken into account by the device when performing the assay. Reagents typically change their properties over a specific period, i.e., there may be an increase or decrease in reactivity or an increase or decrease in signal depending on the storage period of the reagent or batch or other factors. This is typically understood as a dynamic process and can lead to a difference in measurement of up to 20%. Therefore, the reading values of the data points collected during production are particularly prone to variation, especially in the case of reagents stored over a long period, and can invalidate the measurement results.

[0042] In vitro diagnostic devices according to the present invention are typically connected to additional components within a network. Such a network may be an Internet-based or intranet-based network. The connection of the device to additional components can further be established by short-range connections such as Bluetooth, Wi-Fi, ZigBee, etc. To enable data exchange, via a link to the network, the in vitro diagnostic device can be incorporated into a system and connected to other components of the system. Thus, the term "system" as used herein refers to both a single link of one in vitro diagnostic device to a network having additional components, such as a control unit, and a group or multiple in vitro diagnostic devices connected to a network having a control unit (or optionally multiple interactive control units). Depending on the structure and concept, the system can include one or more additional components. For example, various types of devices can be incorporated, and data resources such as reagent manufacturers, software developers, device manufacturers, etc. can be incorporated. In certain embodiments, further, government authorities, such as health authorities, regulatory authorities, or each medical department / laboratory of a clinic, hospital, etc. can be incorporated into the present system, for example, via database access.

[0043] Thus, in a preferred embodiment, the in vitro diagnostic device is connected to a number of other in vitro diagnostic devices, for example, all or most of the in vitro diagnostic devices of a particular type or particular device series, such as those in a particular region, particular city, particular federal state, particular country, or continent, are network connectable, or they are globally network connectable. In a preferred embodiment, the devices are connected to each other as a fleet of the same type.

[0044] It is preferable that a secure data connection be employed within the network or system. An example of the concept of a preferable secure data connection within the scope of the present invention is Smart Remote Services (SRS). In that case, a bi-directional connection of the in vitro diagnostic device to the SRS portal or access server is set up, whereby access to local data stored in the server becomes possible regardless of the location. For example, the SRS support can monitor the performance of the device hardware, its operating time, or possible problems. Similarly, software-based device maintenance can be performed. By virtue of the described bi-directional linking of the in vitro diagnostic device to the network, a control loop for applying an adjustment function or a correction function to the in vitro diagnostic device is generated. The control loop is preferably designed as a closed control loop and is protected from external influences of the secure data connection.

[0045] Regarding a secure data connection on the Internet, within the scope of the present invention, a virtual private network (VPN) that cannot be browsed by third parties is preferably employed.

[0046] According to the present invention, an in vitro diagnostic device is configured to detect deviations of internal calibration / control measurement parameters from defined reference values. The term "calibration / control measurement parameter" as used herein refers to all parameters or measurements collected in an in vitro diagnostic device in relation to the execution of an assay. This includes, for example, parameters or measurements related to assay reagents used to perform in vitro diagnostics, which are collected during the use of a standardized reference substance / calibration substance, before or during the execution of the assay. Further, the internal calibration / control measurement parameters may be device system component parameters, i.e., they can reflect the characteristics of specific system components such as optical relationships, voltage, current, temperature, temperature rise, etc. In another embodiment, an initial measurement of the internal calibration / control measurement parameters is used to determine the deviation. These may be, for example, the first measurement after the device is started up or the measurement before performing the first assay of the operating day or operating shift.

[0047] In another embodiment, a deviation from a calibration curve is detected. The term "calibration curve" as used herein refers to a curve or table for an in vitro diagnostic device that indirectly measures a parameter and indicates a value related to a desired quantity in response to a sensor output value. Such a curve is typically used when the calibration of an in vitro diagnostic device varies greatly with the sample or over time or with use. In that case, the calibration curve typically shows how the analysis signal changes, for example, with the concentration of the reagent or substance to be measured.

[0048] The collected calibration / control measurement parameters or the generated calibration curve are compared, in accordance with the present invention, with the reference values or reference curves established in the in vitro diagnostic device. Such a comparison can preferably be performed by components within the device, such as a so-called offset detector, and various periods, such as time, day, week, month, etc. can be scheduled. "Reference values" are used as comparison standard values and include, for example, batch-dependent target values, technical specification values for the device, assay-dependent values, etc. These values are manually input into the in vitro diagnostic device or transmitted to the device via a network or communication connection. Within the scope of, for example, batch changes or device maintenance, changes to the reference values are typically stored in the in vitro diagnostic device. In that case, the method according to the present invention further results in a change to the reference values by the correction factor of the control loop model described herein.

[0049] For this purpose, in a first step, after detecting the deviation of the calibration / control measurement parameters from the reference values, the measured difference is transmitted to the control unit. The "control unit" may preferably be an electronic component or a computer-assisted component connected to the in vitro diagnostic device via a network link. The control unit is configured to evaluate the deviation of the internal calibration / control measurement parameters from the defined reference values of at least one in vitro diagnostic device. Thus, specifically, the control unit can evaluate the deviation of the defined reference values according to the assay reagent batch used.

[0050] In that case, the difference or deviation of the internal calibration / control measurement parameters for the assay reagent from the reference value, detected by the in vitro diagnostic device, is transmitted to the control unit and compared with the existing data. The comparison can be performed, for example, using the latest data or historical data, for example, over 12 hours, 1, 2, 3, 4, 5, 6 days, 1, 2, 3 weeks, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 months, 1, 2, 3 years ago, etc., or using the data collected over the useful life of the in vitro diagnostic device. Advantageously, the comparison can also be performed using the data of other in vitro diagnostic devices. In that case, either the historical data or the latest data of those devices can be adopted. Such an evaluation can be used to identify the pattern of change, the trend of variation, or the shift in assay performance, or the dynamic process in a number of in vitro diagnostic devices.

[0051] Furthermore or alternatively, the deviation from the specified reference value is evaluated by the control unit according to the value collected or transmitted for the device system component. Here, the latest and historical values of the same device or a number of devices as mentioned above can be evaluated.

[0052] Furthermore or alternatively, the deviation from the specified reference value is evaluated by the control unit according to the value collected or transmitted for the device type. Here, the latest and historical values of all or a number of devices of the same type, possibly of the same construction year, the same maintenance period, etc., can be evaluated.

[0053] By evaluating the deviation according to the device system component or device type, it becomes possible to identify system variations in the device that are caused by the device component or affected by the device type. In this way, it is possible to identify individual devices or device types or device groups that have technical problems, i.e., hardware problems for example. When reproducing the problem, it is possible to respond using an (adjusted) correction of the reference value or to propose alternative measures. The measures can also be, for example, maintenance of the device or devices in the group, replacement of the device component, loading of new software, use of specific reagents, etc. Furthermore, it is possible to warn the user of the device so that the assay results are not used for medical purposes and the test is not repeated using different devices.

[0054] In another embodiment of the present invention, not only internal calibration / control measurement parameters related to assay and device functions, but also specific diagnostic measurement results obtained using patient samples by the assay are transmitted by the in vitro diagnostic device to the control unit. Those measurement results are preferably transmitted in accordance with data protection via an encrypted connection or a secure connection, and also the existing pattern of variation or tendency of fluctuation or shift in assay performance, or a dynamic process in a number of assays of one or a number of in vitro diagnostic devices is evaluated by the control unit. Advantageously, the number of measurement results obtained using patient samples is significantly larger (from 100 to 1000 times) than the number of obtained calibration / control measurement parameter values. Thus, when a statistically significant number of in vitro diagnostic devices can be evaluated and taken into account for data analysis, it is expected that the general distribution patterns of patient results, such as physiological and pathological results, are substantially consistent, so that it is possible to detect the tendency of shift or pattern of change more quickly and accurately, and to improve system performance. In a particular embodiment, data of patient samples measured in an assay, i.e., a "patient assay", can be stored in a data memory or database associated with the control unit to be accessible for further analysis. Furthermore, data obtained from the patient assay can similarly be stored or evaluated as a history, i.e., it is possible to store, compare, evaluate, etc. data from different periods, and by doing so, it is possible to detect a pattern of variation in some cases. By the evaluation, it is possible to identify both device-specific deviations due to, for example, hardware components, and batch-dependent deviations of assay reagents.

[0055] In an embodiment of the present invention, the control unit is configured to receive and evaluate the detected deviations of a number of in vitro diagnostic devices. The control unit is preferably configured as a data analysis unit in a preferred embodiment, i.e., it uses computer-based data evaluation techniques, such as AI-assisted evaluation techniques, data mining techniques, etc. The control unit is connected to one or more databases in other preferred embodiments, and can obtain values and data from the databases and use them to evaluate the transmitted differences of calibration / control measurement parameters or calibration curves from reference values. The database can supply, for example, batch-assisted data, such as target values or initial setting values for each in vitro diagnostic device, hold assay-related data, include the evaluation of other devices connected to the control unit, or make available warning messages from the device manufacturer or other in vitro diagnostic devices regarding, for example, mechanical or technical problems of the device. The database can further include historical or up-to-date data regarding patient assays as described above, for example, data for one, multiple, or a number of in vitro diagnostic devices, or multiple assays performed, optionally using various assay reagent batches for various assays performed.

[0056] Furthermore, the control unit can store data and evaluation results in the database and make them available for other or future evaluation processes or other purposes.

[0057] After evaluation of the difference of the calibration / reference measurement parameters or the calibration curve from the reference value sent to the control unit, the reference value is corrected by the control unit. The control unit of the system according to the invention is accordingly configured to correct the reference value and send it to the in vitro diagnostic device. "Correction" may in this case be an increase or a decrease of the reference value according to the difference sent. Subsequently, the corrected, i.e. increased or decreased, reference value is sent back to the in vitro diagnostic device that reported the difference. Such sending can, as shown in FIG. 1, be carried out via a correction element in a specific embodiment. The in vitro diagnostic device then, i.e. after sending, performs all further assays or tests based on the corrected reference value until a new correction of the reference value, if any, is carried out by the control unit.

[0058] The correction of the reference value can be controlled in a specific embodiment, in particular by a threshold method. In that case, the value, the number of messages, and the variance of the value (for example, by establishing the standard deviation and / or the absolute number of the measured values) beyond which the correction should be carried out can be established. Furthermore, it is possible to select whether a specific correction of the in vitro diagnostic device is sent and / or whether that correction is sent to a group of devices or to all devices.

[0059] The correction of the reference value is preferably carried out by generating a correction factor for that reference value. The term "correction factor", as used herein, refers to a change instruction regarding the reference value used in the in vitro diagnostic device, for example for assay calibration or device values. The change instruction can produce, for example, an increase of the value or a decrease of the value. This can be done by an absolute value indication, a mathematical formula, or a percentage change indication.

[0060] The correction factor can be composed of various partial correction factors or group correction factors, which can, in some cases, be sent individually to and assigned separately to relevant components of the device and relate to various deviation scenarios of the in vitro diagnostic device.

[0061] For example, the reference value can be corrected by a correction factor determined based on individual deviations of the in vitro diagnostic device from the reference value. Such deviations can typically relate to the technical functions of the device or, alternatively, to environmental variables such as device location, temperature on the assay execution date, air humidity, vibration, sunlight exposure, operator personnel, time, etc. The corresponding deviations, and optionally additional parameters, can be confirmed by the device itself or, alternatively, obtained by additional external parameter acquisition at that location, for example when the device does not have a sensor.

[0062] Furthermore, the reference value can be corrected by a correction factor determined based on assay reagent batch-dependent deviations of one or preferably multiple in vitro diagnostic devices from the reference value. Such deviations can, as mentioned earlier, be variation patterns over the shelf life of the batch or for batches employed in multiple in vitro diagnostic devices. Typically, such deviations are established over a fixed period and may change dynamically. Correspondingly, the correction factor needs to be tracked and adjusted to the latest deviations.

[0063] Furthermore, the reference value can be corrected by a correction factor determined based on deviations of the measurement data of the patient assay from the prior measurement data, control, and / or calibration of the patient assay. Such deviations can preferably be identified, as mentioned earlier, by evaluating the assay data of a large number of patients at a certain location or multiple, preferably numerous locations, i.e., assays performed using a large number of in vitro diagnostic devices. Preferably, the evaluation of the patient assay data includes a comparison with further evaluation results, such as assay reagent deviations and device-specific deviations, to facilitate the assignment of deviations to specific problem areas.

[0064] Furthermore, the reference value is corrected by a correction factor determined based on the device type-dependent deviations of a plurality of in vitro diagnostic devices from the reference value. The device type-dependent deviations are typically variations caused by specific components or characteristics of the in vitro diagnostic device, and the variations are identifiable in all or many in vitro diagnostic devices, such as a specific type, year of construction, place of manufacture, or place of production. The patterns identified in the behavior of the deviations can be compensated for by the correction factors for all corresponding devices.

[0065] Furthermore, the reference value can be corrected by a correction factor determined based on the device system component-dependent deviations of a plurality of in vitro diagnostic devices from the reference value. The device system components can be checked by hardware checks or by technical measurements of parameters such as optical relationships, voltage, current, temperature, or in the form of self-tests of the device regarding deviations from the reference value. Such deviations can be device-specific, i.e., occur only in a specific device or a group of devices. The corresponding correction factors are sent to that individual device or group of devices. The transmission of the individual correction factors can be performed, in a particular embodiment, in response to exceeding / falling below a predetermined threshold.

[0066] Generally, one individual deviation of the parameters described herein from the reference value can be a signal regarding a malfunction, such as a specific device or a reagent specifically used. If an individual deviation occurs but cannot be found as a variation pattern in other in vitro diagnostic devices, preferably, instead of a correction factor, a warning message is sent to the in vitro diagnostic device and / or the operator responsible person.

[0067] Furthermore, the reference value can be corrected by a correction factor determined based on the deviation of the measurement or calibration / control measurement parameters from the measurement or calibration / control measurement parameters in a number of in vitro diagnostic devices. The deviation from the calibration / control measurement parameters in a number of in vitro diagnostic devices can be evaluated by a control unit connected to the number of devices. By the doubling effect with a statistically evaluable amount of data, the tendency of the deviation can be determined more quickly and accurately. Correspondingly, the correction factor can be finely adjusted for all devices in the group to be analyzed. In this way, a very efficient closed control loop is established, which eliminates the need for manual or individual correction of the corresponding reference value and at the same time enables real-time monitoring to efficiently avoid errors and value deviations.

[0068] Furthermore, the reference value can be corrected by a correction factor determined based on a combination of deviations dependent on device system components, deviations dependent on assay reagent batches, and / or deviations from the measurement data of patient assays. In other embodiments, the correction factor can be determined by combining with further deviations as mentioned above. In that case, the correction factor can be transmitted to the in vitro diagnostic device as an individual correction factor and can be implemented by the device software so that the measurement variations are compensated in all affected areas, or the correction factor can be transmitted as a group of partial correction factors for each deviating component.

[0069] In another preferred embodiment of the present invention, at least one in vitro diagnostic device is configured to determine, at regular time intervals, the deviation of an internal calibration / control measurement parameter from a defined reference value as previously defined. These time intervals may vary depending on the parameter to be measured, device type, assay type, reagent, reagent expiration date, or other factors. For example, the determination can be made once a day, once every 12 hours, once a week, once every 2, 3, 4, 5, or 6 days, once every 2, 3 weeks, once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 months, once a year, etc., or once during the useful life or a part of the useful life of the in vitro diagnostic device, assay reagent, or system component. Further, the determination can be made after a specific number of assays have been performed, such as after the 10th, 20th, 30th, 40th, 50th, 100th, 500th assay, etc., for each operating shift, for each operator change. The determination can be initiated by the in vitro diagnostic device itself or can be started by a control unit.

[0070] In another aspect, the present invention relates to a method for modifying a defined reference value of an internal calibration / control measurement parameter of at least one in vitro diagnostic device, wherein the internal calibration / control measurement parameter measured in the in vitro diagnostic device has a deviation from the reference value. In that case, the method preferably comprises sending the deviation to at least one control unit as defined herein, evaluating the deviation in the control unit, and sending the modified reference value based on the deviation to the in vitro diagnostic device in which the deviation was detected.

[0071] In a particular embodiment, the measurement data of the patient assay is further sent to the control unit as shown in the context of the system according to the present invention.

[0072] In a particularly preferred embodiment, the deviation from the initial measurement of the internal calibration / control measurement parameter and / or the deviation of the internal calibration / control measurement parameter from a defined reference value are sent at defined time intervals. For example, sending in this way can be done once a day, once every 12 hours, once a week, once every 2, 3, 4, 5, 6 days, once every 1, 2, 3 weeks, once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 months, once a year, etc., or once during the useful life or a part of the useful life of an in vitro diagnostic device, assay reagent, or system component.

[0073] In certain steps, the method according to the invention involves transmitting and evaluating the deviation of the internal calibration / control measurement parameter or the device system component parameter associated with the assay reagent used to perform in vitro diagnostics as defined herein. Further, as defined herein, it includes transmitting and evaluating the deviation from the reference value defined according to the assay reagent batch, device system component, and / or device type used. Preferably, this includes the internal calibration / control measurement parameter or its deviation of a number of in vitro diagnostic devices.

[0074] In a particularly preferred embodiment of the method according to the invention, the reference value defined herein is corrected by a correction factor. The correction factor is determined based on (i) the individual deviation of the in vitro diagnostic device from the reference value, (ii) the deviation of the assay reagent batch of a plurality of in vitro diagnostic devices from the reference value, (iii) the deviation of the measurement data of the patient assay from the prior measurement data of the patient assay, (iv) the deviation of the device type of a plurality of in vitro diagnostic devices from the reference value, (v) the deviation of the device system component of a plurality of in vitro diagnostic devices from the reference value, (vi) the deviation of the measurement or calibration / control measurement parameter from the measurement or calibration / control measurement parameter in a number of in vitro diagnostic devices, and / or (vii) a combination of the deviation of the device system component, the deviation of the assay reagent batch, and / or the deviation of the measurement data of the patient assay, as mentioned in detail above.

[0075] The examples and figures are shown for illustrative purposes. Therefore, it should be understood that those examples and figures should not be construed as limiting. Those skilled in the art can clearly envision further modifications to the principles described herein.

Examples

[0076] Example 1 The following description relates to an aPTT assay using a first reagent batch (batch #1). In this case, batch-specific values were assigned to the assay at the time of manufacturing completion. The assay shows an upper normal value (31 seconds) for a standardized physiological sample.

[0077] Using this assay and batch, it was found that the average value of the results continuously increased over a three-month period for all the measured data obtained from an in vitro diagnostic system that employed a control substance intended to actually yield reproducibility of the same value.

[0078] The offset detector used showed an increase of 2.7 seconds over a three-month period.

[0079] If it continues to increase linearly over an 18-month operating time, this would mean that an artificial incorrect result would increase from the initial 31 seconds by 18.9 seconds to 49.9 seconds.

[0080] The offset detector calculated the difference, and the control element determined the resulting correction factor therefrom. Therefore, it could be shown that the assay application corrected the measured values despite the increasing signal value and supplied them to the laboratory and medical staff (see also Figure 3).

Explanation of Symbols

[0081] 1 In vitro diagnostic device 2 Assay 3 Control unit 4 Correction element 5 Additional in vitro diagnostic devices 20 Application 21 Further devices 22 Network

Claims

1. A system comprising: At least one in vitro diagnostic device configured to perform a diagnostic assay, the in vitro diagnostic device being configured to detect a deviation of an internal calibration / control measurement parameter from a defined reference value or calibration curve and send it to a control unit; At least one control unit bidirectionally connected to at least one of the in vitro diagnostic devices and configured to evaluate a deviation of an internal calibration / control measurement parameter from a defined reference value of at least one in vitro diagnostic device, the control unit further accessing data from a database for evaluation; Including To enable the in vitro diagnostic device to supply consistent result values, the control unit is configured to correct the reference value against which a deviated internal calibration / control measurement parameter was detected and transmit the corrected reference value to the in vitro diagnostic device that detected the deviation. The control unit is configured to evaluate a deviation from a defined reference value depending on the assay reagent batch, device system component, or device type used. The evaluation includes a comparison of the deviation of the internal calibration / control measurement parameter and a comparison of the measurement data of the patient assays of a number of in vitro diagnostic devices. The system.

2. The system according to claim 1, wherein the internal calibration / control measurement parameter is a parameter related to an assay reagent used to perform the in vitro diagnosis.

3. The system according to claim 1, wherein the internal calibration / control measurement parameter is a device system component parameter.

4. The system according to any one of claims 1 to 3, wherein at least one in vitro diagnostic device is further configured to send measurement data of a patient sample measured in an assay (patient assay) to the control unit.

5. The system according to claim 4, wherein the control unit is further configured to evaluate the measurement data of the patient assay using prior measurement data, controls, and / or calibrations of the patient assay.

6. The control unit is configured to access a database that includes data regarding measurement or calibration / control measurement parameters associated with assay reagents and / or includes data regarding device system component parameters and / or includes data regarding patient assays, according to the system of any one of claims 1 to 5.

7. The reference value is corrected by a correction factor determined based on (i) individual deviations of the in vitro diagnostic device from the reference value, (ii) assay reagent batch-dependent deviations of a plurality of in vitro diagnostic devices from the reference value, (iii) deviations of the measurement data of the patient assay from the prior measurement data of the patient assay, (iv) device type-dependent deviations of a plurality of in vitro diagnostic devices from the reference value, (v) device system component-dependent deviations of a plurality of in vitro diagnostic devices from the reference value, (vi) deviations of measurement or calibration / control measurement parameters from measurement or calibration / control measurement parameters in a number of in vitro diagnostic devices, and / or (vii) a combination of device system component-dependent deviations, assay reagent batch-dependent deviations, and / or deviations from the measurement data of the patient assay, according to the system of any one of claims 1 to 6.

8. At least one in vitro diagnostic device is configured to detect a deviation of internal calibration / control measurement parameters from a defined reference value once a year, once every 12 hours, once a day for 1, 2, 3, 4, 5, 6 days, once a week for 1, 2, 3 weeks, once a month for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 months, or once during the service life or a part of the service life of the in vitro diagnostic device, assay reagent, or system component, and send it to the control unit, according to the system of any one of claims 1 to 7.

9. A method for correcting a defined reference value of internal calibration / control measurement parameters of at least one in vitro diagnostic device, wherein the internal calibration / control measurement parameters measured in the in vitro diagnostic device have a deviation from the reference value, the method includes: sending the deviation to at least one control unit; evaluating the deviation in the control unit; sending the reference value corrected based on the deviation to the in vitro diagnostic device that detected the deviation. The measurement data of the patient assay is further sent to the control unit, and the deviation from the initial measurement of the internal calibration / control measurement parameters, the deviation of the internal calibration / control measurement parameters from the specified reference value, is detected once at 1, 12 hours, 1, 2, 3, 4, 5, 6 days, 1, 2, 3 weeks, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 months, 1 year, or once during the service life, or a part of the service life, of the in vitro diagnostic device, assay reagent, or system component of the in vitro diagnostic device, and is sent, The evaluation of the deviation from the specified reference value is performed according to the assay reagent batch, device system component, and / or device type used, The evaluation includes a comparison of the deviations of the internal calibration / control measurement parameters of a number of in vitro diagnostic devices, The said method.

10. The method according to claim 9, wherein the internal calibration / control measurement parameter is a parameter related to the assay reagent used to perform the in vitro diagnosis, or a device system component parameter.

11. The reference value is corrected by a correction factor determined based on (i) the individual deviation of the in vitro diagnostic device from the reference value, (ii) the batch-dependent deviation of the assay reagent of a plurality of in vitro diagnostic devices from the reference value, (iii) the deviation of the measurement data of the patient assay from the previous measurement data of the patient assay, (iv) the device type-dependent deviation of a plurality of in vitro diagnostic devices from the reference value, (v) the device system component-dependent deviation of a plurality of in vitro diagnostic devices from the reference value, (vi) the deviation of the measurement or calibration / control measurement parameter from the measurement or calibration / control measurement parameter in a number of in vitro diagnostic devices, and / or (vii) a combination of the device system component-dependent deviation, the assay reagent batch-dependent deviation, and / or the deviation from the measurement data of the patient assay. The method according to claim 9 or 10.

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