Determining interference criticality based on analyte and cell-free hemoglobin concentration

Abstract

To provide an apparatus for automatically measuring analyte concentration in a liquid sample, and more specifically, an apparatus for automatically measuring the analyte concentration in the liquid sample and determining the criticality of an interferent.SOLUTION: There is presented an apparatus (100) for automatically measuring analyte concentration in a liquid sample (102) comprising the analyte and cell-free hemoglobin and for automatically determining a cell-free hemoglobin interference criticality. The apparatus comprises one or more sensors (104) for measuring the analyte concentration in the liquid sample and cell-free hemoglobin concentration in the liquid sample, and further comprises a data processing device (106) comprising a processor. The data processing device (106) is configured to determine the cell-free hemoglobin interference criticality on the basis of the cell-free hemoglobin concentration and the analyte concentration, and to output a signal (108) indicative of the cell-free hemoglobin interference criticality at least in the case where the cell-free hemoglobin interference criticality is within a predetermined range.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to an apparatus for automatically measuring an analyte concentration in a liquid sample, and more particularly to an apparatus for automatically measuring an analyte concentration in a liquid sample and determining the criticality of interferents, and further to corresponding methods and computer program products. [Background technology]

[0002] Determining the concentration of an analyte in a liquid sample is relevant in many applications, for example in diagnostic testing of blood samples, obtaining information from a blood sample about parameters indicative of training status or nutritional value, and / or testing for certain substances in a blood sample, such as alcohol, narcotics, or performance enhancing drugs. However, the measured analyte concentration in a sample may deviate from the true concentration, which may be understood to be the concentration of said analyte in a subject (such as the person from whom the sample was taken). For example, certain substances known as interfering substances may interfere with the measurement of the concentration of an analyte, leading to an erroneous measurement of the concentration of the analyte, possibly even to significant levels. As a result, the interference may result in an erroneous result of the measurement of the concentration of the analyte and / or may make resource-demanding retesting necessary. As another example, hemolysis releases intercellular components (such as components identical to the analyte whose concentration in the subject's blood is of interest) from the red blood cells of the blood sample into the plasma phase, which may, for example, interfere with the measurement of the concentration of some analytes in a blood sample, in the sense that the measured concentration in the sample deviates from the true concentration in the subject. Summary of the Invention

[0003] It is an object of embodiments of the present invention to provide improved devices, methods, and computer program products for automatically measuring an analyte concentration in a liquid sample comprising acellular hemoglobin, and in particular to provide devices, methods, and computer program products for automatically measuring an analyte concentration in a liquid sample comprising acellular hemoglobin, which may reduce or eliminate the adverse effects of erroneous results in the measurement of the concentration of the analyte and / or may at least partially obviate the need for retesting. This specification includes the disclosure of the following inventions. [Item 1] An apparatus (100) for automatically measuring an analyte concentration in a liquid sample (102) containing an analyte and cell-free hemoglobin, and for automatically determining a cell-free hemoglobin interference threshold, the apparatus comprising: One or more sensors (104), the analyte concentration in the liquid sample, and A cell-free hemoglobin concentration in the liquid sample one or more sensors (104) for measuring A data processing device (106) comprising a processor, The cell-free hemoglobin interference threshold is the cell-free hemoglobin concentration, and The analyte concentration Based on the decision, a data processing device (106) configured to output a signal (108) indicative of the acellular hemoglobin interference threshold at least if the acellular hemoglobin interference threshold is within a predetermined range; An apparatus (100). [Item 2] The device (100) of item 1, arranged at a sample inlet, e.g., a single sample inlet, for receiving the liquid sample in the form of a whole blood sample including red blood cells, and for measuring at least the cell-free hemoglobin concentration in at least a portion of the liquid sample that contains or is in liquid communication with the red blood cells. [Item 3] The apparatus (100) of items 1 or 2, further configured to measure at least the analyte concentration in at least the same portion of the liquid sample in which the cell-free hemoglobin concentration was measured, and / or in a portion of the sample in liquid communication with at least the portion of the liquid sample in which the cell-free hemoglobin concentration was measured. [Item 4] The device (100) according to any one of items 1 to 3, arranged to measure the analyte concentration in the liquid sample and the cell-free hemoglobin concentration in the liquid sample at spatial positions less than 1 m, such as less than 75 cm, such as less than 50 cm, such as less than 25 cm, such as less than 10 cm, such as less than 1 cm, from each other, e.g., a maximum dimension of the device is less than 2 m, such as 1 m or less, such as 75 cm or less. [Item 5] An apparatus (100) according to any one of Items 1 to 4, configured to receive at a sample inlet a liquid sample in the form of a whole blood sample comprising red blood cells at a first time point t1, and to output at a second time point t2 a signal (108) indicative of the acellular hemoglobin interference threshold if at least the acellular hemoglobin interference threshold is within a predetermined range, wherein the time period between the first time point and the second time point is 10 minutes or less, such as 5 minutes or less, for example 2 minutes or less, for example 1 minute or less, for example 45 seconds or less, for example 35 seconds or less, for example 30 seconds or less, for example 10 seconds or less. [Item 6] The device (100) of any one of Items 1 to 5, further comprising a porous element, such as a porous mirror, and configured to measure at least the cell-free hemoglobin concentration in a portion of the liquid sample positioned within one or more pores of the porous element. [Item 7] The device (100) according to any one of Items 1 to 6, wherein the analyte concentration is a potassium ion concentration. [Item 8] The data processing device (106) determining a cell-free hemoglobin interference threshold based on said analyte concentration; determining an cell-free hemoglobin interference value based on the cell-free hemoglobin concentration; comparing the cell-free hemoglobin interference value to the cell-free hemoglobin interference threshold; and determining the cell-free hemoglobin interference threshold based on a result of the comparison; The apparatus (100) according to any one of items 1 to 7, configured to determine the acellular hemoglobin interference threshold by: [Item 9] The apparatus (100) of Item 8, wherein the cell-free hemoglobin interference threshold based on analyte concentration is an absolute value, e.g., a function describing the cell-free hemoglobin interference threshold as a function of the analyte concentration is non-linear. [Item 10] The apparatus (100) of Item 8, wherein the cell-free hemoglobin interference threshold based on an analyte concentration is a relative value that is relative to the analyte concentration, e.g., a function describing the cell-free hemoglobin interference threshold as a function of the analyte concentration is non-stationary, e.g., non-linear. [Item 11] The data processing device (106) determining a cell-free hemoglobin concentration threshold based on said analyte concentration; comparing the cell-free hemoglobin concentration or a parameter based on the cell-free hemoglobin concentration to the cell-free hemoglobin concentration threshold; and determining the cell-free hemoglobin interference threshold based on a result of the comparison; The apparatus (100) according to any one of items 1 to 10, configured to determine the acellular hemoglobin interference threshold by: [Item 12] The apparatus (100) of Item 11, wherein the cell-free hemoglobin concentration threshold based on the analyte concentration is an absolute value, e.g., a function describing the cell-free hemoglobin concentration threshold as a function of the analyte concentration is non-linear. [Item 13] The apparatus (100) of Item 11, wherein the cell-free hemoglobin concentration threshold based on the analyte concentration is a relative value that is relative to the analyte concentration, e.g., a function describing the cell-free hemoglobin concentration threshold as a function of the analyte concentration is non-stationary, e.g., non-linear. [Item 14] The apparatus (100) of Item 11, wherein the cell-free hemoglobin threshold is a function of the analyte concentration, and the function is non-stationary with respect to analyte concentration, such as varying numerically as analyte concentration increases within at least one analyte concentration interval, e.g., strictly increasing within at least one analyte concentration interval having a range greater than zero, a function result that increases as analyte concentration increases, or that decreases as analyte concentration increases. [Item 15] The apparatus (100) of any one of Items 11 to 14, wherein the cell-free hemoglobin threshold is a function of the analyte concentration, and the function varies numerically as the analyte concentration increases within at least one analyte concentration interval, e.g., strictly increases within at least one analyte concentration interval having a range greater than zero, the function result is non-linear with respect to analyte concentration, e.g., increases as the analyte concentration increases, or decreases as the analyte concentration increases, within at least one analyte concentration interval having a range greater than zero. [Item 16] The data processing device (106) is operably connected to a storage device (110). The storage device is a predefined categorization scheme, e.g., the predefined categorization scheme allows for categorizing the liquid sample based on analyte concentration; The data processing device (106) determining a measured category of the liquid sample based on the analyte concentration, such as attributing the analyte concentration to a particular measured clinical picture; determining an adjusted concentration, such as an adjusted analyte concentration, the adjusted concentration being adjusted for interfering effects of the cell-free hemoglobin, determining an adjusted concentration based on the analyte concentration, wherein the interference effect of the cell-free hemoglobin is based on the cell-free hemoglobin concentration; determining an adjusted category for the liquid sample based on the adjusted analyte concentration, such as attributing the analyte concentration to an adjusted specific clinical picture; and determining the cell-free hemoglobin interference threshold based on a degree of difference between the measured category and the adjusted category; 16. The apparatus (100) according to any one of items 1 to 15, configured to determine the acellular hemoglobin interference threshold by: [Item 17] The acellular hemoglobin interference threshold is either low or high, and the predefined categorization scheme is one-dimensional and includes at least three categories, and the acellular hemoglobin interference threshold is: low if the measured category and the adjusted category are the same or adjacent within the predefined categorization scheme; Item 17. The apparatus (100) according to item 16, wherein if the measured category and the adjusted category are not separated by at least one category within the predefined categorization scheme, then high. [Item 18] The analyte concentration is Potassium ion, Sodium ion, Calcium ions, Chloride ion, Creatinine, and Lactic acid 18. The device (100) according to any one of items 1 to 17, wherein the concentration of the analyte is selected from the group consisting of: [Item 19] The analyte concentrations are a plurality of analyte concentrations of analytes, for at least two of the analytes: The data processing device (106) The cell-free hemoglobin interference threshold is the cell-free hemoglobin concentration, and The analyte concentration Based on the decision, configured to output a signal (108) indicative of the acellular hemoglobin interference threshold at least when the acellular hemoglobin interference threshold is within a predetermined range; 19. The apparatus (100) according to any one of items 1 to 18, wherein the relationship between the cell-free hemoglobin interference threshold and the analyte concentration is unique for at least two analytes, and is different for each analyte. [Item 20] The device further comprises a user interface (112) arranged to receive user input, The data processing device comprises: 20. The apparatus (100) of any one of items 1 to 19, configured to determine the cell-free hemoglobin interference threshold based on the user input. [Item 21] For at least one first analyte concentration, the first change in the cell-free hemoglobin interference threshold changes as the cell-free hemoglobin concentration increases at the first cell-free hemoglobin concentration; for at least one second analyte concentration, the second change in the cell-free hemoglobin interference threshold changes with increasing cell-free hemoglobin concentration at the second cell-free hemoglobin concentration; The first change is substantially the same as, or is identical to, the second change, such that the first change and the second change each correspond to exceeding a cell-free hemoglobin threshold. the law of nature, the first analyte concentration is less than the second analyte concentration; 21. The apparatus (100) according to any one of items 1 to 20, wherein the first acellular hemoglobin concentration is different from the second acellular hemoglobin concentration, e.g., is smaller or larger than the second acellular hemoglobin concentration. [Item 22] The device, for example a blood gas analyzer, comprises: Carbon dioxide, e.g. CO2, Oxygen, e.g., O2, and pH 22. The apparatus (100) according to any one of items 1 to 21, further arranged to measure the concentration in the liquid sample of one or more or all of the following: [Item 23] A method (700) for automatically measuring an analyte concentration in a liquid sample (102) containing an analyte and acellular hemoglobin, and for automatically determining acellular hemoglobin interference threshold, comprising: a. determining (720) the analyte concentration in the liquid sample; b. measuring the concentration of cell-free hemoglobin in the liquid sample (722); c. a data processing device (106) having a processor, the analyte concentration, The cell-free hemoglobin concentration providing a d. Using said data processing device, the cell-free hemoglobin concentration, and The analyte concentration and automatically determining (724) the cell-free hemoglobin interference threshold based on e. outputting from said data processing device a signal indicative of said acellular hemoglobin interference threshold at least if said acellular hemoglobin interference threshold is within a predetermined range (726); A method (700) comprising: [Item 24] The determination of the acellular hemoglobin interference threshold is Further based on a predefined categorization scheme, for example, the predefined categorization scheme allows for categorizing the liquid sample based on analyte concentration; The method comprises: determining a measured category of the liquid sample based on the analyte concentration, such as attributing the analyte concentration to a particular measured clinical picture; determining an adjusted concentration, such as an adjusted analyte concentration, based on the analyte concentration, such as the measured analyte concentration, where the adjusted concentration is adjusted for interfering effects of the cell-free hemoglobin, and the interfering effects of the cell-free hemoglobin are based on the cell-free hemoglobin concentration; determining an adjusted category for the liquid sample based on the adjusted analyte concentration, such as attributing the analyte concentration to an adjusted specific clinical picture; and determining a cell-free hemoglobin interference threshold based on a degree of difference between said measured category and said adjusted category; 24. The method (700) according to claim 23, comprising determining the cell-free hemoglobin interference threshold by: [Item 25] The liquid sample (102) is at least partially, for example partially or entirely, Samples containing cells such as red blood cells, a sample derived from a sample containing cells such as red blood cells; a whole blood sample, such as a human whole blood sample, or 25. The method according to item 23 or 24, wherein the sample (600) is derived from a whole blood sample, such as serum or plasma, e.g., is a diluted whole blood sample and / or is a fraction of a human whole blood sample, e.g., is derived from a human whole blood sample. [Item 26] A computer program, such as a computer program product, which, when executed by a computer, receiving first information based on an analyte concentration; receiving second information based on the cell-free hemoglobin concentration; Cell-free hemoglobin interference criticality, the cell-free hemoglobin concentration, and The analyte concentration and outputting a signal indicative of the acellular hemoglobin interference threshold at least if the acellular hemoglobin interference threshold is within a predetermined range (726); A computer program comprising instructions for causing a computer to carry out the steps of:

[0004] According to a first aspect, the present invention provides an apparatus for automatically measuring an analyte concentration in a liquid sample comprising an analyte and cell-free hemoglobin, and for automatically determining an cell-free hemoglobin interference threshold, said apparatus comprising: One or more sensors, the analyte concentration in the liquid sample, and Cell-free hemoglobin concentration in liquid samples one or more sensors for measuring A data processing device comprising a processor, Cell-free hemoglobin interference criticality, Cell-free hemoglobin concentration, and Analyte concentration Based on the decision, a data processing device configured to output a signal indicative of the acellular hemoglobin interference threshold at least if the acellular hemoglobin interference threshold is within a predetermined range; Equipped with.

[0005] A possible advantage of the present invention is that by basing the cell-free hemoglobin interference threshold on both the cell-free hemoglobin concentration and the analyte concentration, the data processing device can determine the cell-free hemoglobin interference threshold according to a predetermined instruction (such as the relationship between the cell-free hemoglobin interference threshold and the analyte concentration). The object of the present invention is to allow for the consideration of stationary, e.g., predetermined commands that entail non-linear relationships, thereby improving the applicability of the cell-free hemoglobin interference criteria.

[0006] For example, the present invention allows the acellular hemoglobin interference threshold to be independent of the acellular hemoglobin concentration and the analyte concentration, which may result in both too high and too low acellular hemoglobin interference thresholds in various scenarios. If the acellular hemoglobin interference threshold were dependent on only one of the acellular hemoglobin concentration and the analyte concentration, the acellular hemoglobin interference threshold may be too high for some values ​​of the other concentration and too low for other values ​​of the other concentration. Thus, a compromise had to be made between having too many cases of too high acellular hemoglobin interference threshold values ​​and too many cases of too low acellular hemoglobin interference threshold values. The present invention allows the determination of the acellular hemoglobin interference threshold to be improved or optimized for any pair or value of analyte concentration and acellular hemoglobin concentration.

[0007] The present invention may be advantageous as an aid to decisions about, for example, how to respond to a particular measured concentration of an analyte, such as aiding in such decisions in a fast, predetermined, systematic, and / or error-free manner, and / or in a manner that does not require expert skill (which may be particularly relevant, for example, in a point-of-care context).

[0008] An 'apparatus for automatically measuring an analyte concentration in a liquid sample' may be understood as any apparatus that is capable of measuring an analyte concentration in a liquid, e.g. in a liquid sample, automatically - e.g. without requiring human intervention after providing the liquid sample to the apparatus - e.g. an apparatus that can probe optical, electrical and / or other properties of the liquid and / or of analytes in the liquid and derive information about the analyte concentration.

[0009] An 'analyte' is understood to be any entity, substance or composition, which may in particular be an atom, ion and / or molecule. An 'analyte' is understood to encompass a group of analytes, or a group of entities, substances or compositions, which share one or more properties, e.g. chemical properties or structural or physical properties.

[0010] 'Acellular hemoglobin' (cfHb) is understood as commonly in the art and specifically as hemoglobin outside of red blood cells. Acellular hemoglobin (also called naked hemoglobin) is hemoglobin that is not enclosed in red blood cells. Acellular hemoglobin can be released into plasma as a result of hemolysis, which is the rupture (lysis) of red blood cells (erythrocytes) and release of their contents (cytoplasm) into the surrounding fluid (e.g., plasma). Hemolysis can occur in vivo or in vitro (inside or outside the body).

[0011] 'Cell-free hemoglobin interference' refers to the effect or influence that cell-free hemoglobin in a liquid sample has or may have or may represent or represents a measured concentration of an analyte, such as a relative or absolute change in concentration of the analyte (e.g. using the same units or quantity per unit as the analyte concentration) (the change in concentration may be obtained as the difference between the measured concentration - affected by interference - and the true concentration or an estimate of the true concentration, optionally obtained by inferring an estimated contribution from the interference), and / or the effect or influence that cell-free hemoglobin in a liquid sample has on another high demand concentration, such as the concentration of a previous sample (such as in the patient and / or before ex vivo / in vitro hemolysis). It is understood that the effect of interferences is an influence. The effect of interferences may be due to the sensor being unable to distinguish between the analyte and the interferences, and therefore the sensor erroneously attributes the measured contribution from the interferences to the analyte, and therefore provides a concentration based only on the true analyte concentration, rather than based on the interference and the true analyte concentration. However, the effect of interferences may also be due to the interferences being (homologously) bound to the interference amount of the analyte (thus, although the interferences are present in the liquid sample, they should nevertheless be ignored for the purpose of estimating the true analyte concentration, but the sensor takes the interferences into account for natural reasons). For example, the analyte concentration (such as potassium ion concentration) to be determined in a blood sample is the in vivo analyte concentration (i.e., the analyte concentration in, for example, the person from whom the blood sample is taken), but cell-free hemoglobin may be (homologously) bound to the amount of analyte (such as potassium ion) that is released into the blood sample after the blood sample is drawn, and thus the measured (and actual, real) concentration of potassium ion in the blood sample will overestimate the true in vivo analyte concentration (of potassium ion).

[0012] 'Interference' is therefore understood as is common in the art, including but not limited to, not including one entity interfering with the measurement of the concentration of another entity, nor one entity expressing a change in the concentration of another entity relative to a previous (high demand) concentration of such other entity.

[0013] In embodiments (such as those in which the analyte is potassium ion), 'interference' is understood to refer to one entity expressing a change in concentration of another entity relative to a previous (high demand) concentration of such other entity. For example, in these embodiments, the cell-free hemoglobin interference threshold may be exchanged, for example, for the 'cell-free hemoglobin homology (effect) threshold'.

[0014] Besides releasing hemoglobin into the surrounding fluid, hemolysis may additionally release other substances, such as analytes, and therefore, when hemolysis occurs outside the body, measurements of the concentration of such substance(s) (analyte(s)) may not represent the true value of the concentration in the person (patient) from whom the sample was originally taken.

[0015] Throughout this application, this effect will be referred to as interference for convenience. However, for completeness, it is noted that according to embodiments of the present invention, 'interference' is not interference in the sense that the measured concentration of the sample is erroneous relative to the true concentration of the analyte in the sample due to interference, because hemoglobin is not such that it impedes (interferes with) the measurement of the true concentration of the analyte, but it simply indicates that the true sample concentration is (possibly) different from the true patient concentration. For this reason, the use of 'interference (critical)' in and throughout this application (except for this paragraph) may be interchanged with 'homology effect (critical)', such as 'cell-free hemoglobin homology effect (critical)', in the context of those embodiments (e.g. for the 'interference' of cell-free hemoglobin on potassium), with a view to indicating that the measured analyte concentration in a sample does not necessarily deviate from the true sample concentration, but may deviate from the true patient concentration due to homology (explained in more detail below).

[0016] 'Cell-free hemoglobin interference criticality' is understood as a measure of the extent to which cell-free hemoglobin interference is significant for estimating (based on the measured analyte concentration) the true analyte concentration, such as the true value in the liquid sample or the true value of the liquid sample before perturbation (e.g., in the patient from whom the sample is taken or derived), and / or for enabling a meaningful use or interpretation of the analyte concentration, e.g., with respect to using the analyte concentration to estimate a parameter (such as morbidity or mortality). For example, a predefined instruction may be to determine the cell-free hemoglobin interference based on a ratio or comparison of the estimated cell-free hemoglobin interference to the analyte concentration. The predefined instructions may be set to evaluate the cell-free hemoglobin interference threshold (e.g., the cell-free hemoglobin interference threshold may be expressed as a percentage of the analyte concentration), e.g., a low analyte concentration results in a high cell-free hemoglobin concentration, while a high analyte concentration results in a low cell-free hemoglobin interference threshold. Alternatively, e.g., perhaps according to more sophisticated predefined instructions, the predefined instructions may require that the cell-free hemoglobin interference threshold is exclusively 'low' if the impact of cell-free hemoglobin interference on the parameter is below a certain impact value (and otherwise, i.e., the cell-free hemoglobin interference threshold is exclusively 'high' if said impact is equal to or exceeds said impact value), which entails that the cell-free hemoglobin interference threshold depends on the difference in the parameter with and without (estimated) cell-free hemoglobin interference.

[0017] The cell-free hemoglobin interference threshold may be expressed as a fraction or percentage of the analyte concentration and may be non-linear or linear, eg, constant or non-constant, eg, directly proportional or offset, with respect to the analyte concentration.

[0018] Alternatively, the cell-free hemoglobin interference threshold may be expressed absolutely and may be non-linear or linear, eg, constant or non-constant, eg, directly proportional or offset, with respect to the analyte concentration.

[0019] The (functional) relationship between the parameter and the analyte concentration may be non-stationary, such as non-linear. By 'non-linear' in the context of this application is generally understood a relationship between entities such as x and y that cannot be expressed in the form y=ax, where a is a constant, e.g., cannot be expressed in the form y=ax+b, where a and b are constants. For example, y can be an acellular hemoglobin interference threshold (for comparison with acellular hemoglobin interference for purposes of assessing acellular hemoglobin interference criticality) and x can be an analyte concentration.

[0020] The cell-free hemoglobin interference criticality may be qualitative, such as binary, providing a sample space with only two mutually exclusive categories (or possible result values), e.g., 'high' and 'low', '0' and '1', or 'reveal' (e.g., providing an instruction to release the analyte concentration for clinical diagnosis) or 'retest' (e.g., an instruction to retest due to the risk associated with too high cell-free hemoglobin interference).

[0021] Alternatively, the cell-free hemoglobin sample space may be according to an ordinal measurement scale (where measurements may be classified into ranked groups, e.g., three, or four, or five, or more groups (or result values) associated with increasing cell-free hemoglobin interference criticality), or according to a time interval or ratio measurement scale in which the cell-free hemoglobin interference criticality may be quantified, such as by assuming a numerical score, e.g., the numerical score is calculated objectively based on the measured concentrations (and optionally further values ​​according to a predefined order). For example, the cell-free hemoglobin interference criticality may be expressed as (e.g., any) real or integer number within an interval, e.g., [0;100], with lower numbers indicating lower criticality and increasingly higher numbers indicating increasing criticality.

[0022] 'Acellular hemoglobin interference threshold' should be understood to be interchangeable with a threshold such as a 'critical threshold' or 'analyte-specific critical threshold' or 'decision support threshold' or 'decision decision threshold' that is determined according to predetermined instructions and based on the analyte concentration and the acellular hemoglobin concentration.

[0023] The predefined instructions may include information that determines how the cell-free hemoglobin interference threshold should be determined based on the cell-free hemoglobin concentration and the analyte concentration. The data processing device includes or has access to predefined instructions (e.g., via a digital storage device operatively included in the data processing device and / or connected to the processor), for example, allowing the data processing device to take in the cell-free hemoglobin concentration and the analyte concentration as inputs and determine the cell-free hemoglobin interference threshold based on the cell-free hemoglobin concentration and the analyte concentration according to the predefined instructions. Alternatively, the predefined instructions can be implemented as or based on an algorithm or a look-up table. The predefined instructions can be implemented, for example, as an cell-free hemoglobin threshold that depends on the analyte concentration, for example, the threshold is implemented as a function of the analyte concentration, and the cell-free hemoglobin interference threshold depends in a binary manner on whether the measured cell-free hemoglobin exceeds the threshold. Alternatively, the predefined instructions may be implemented as an algorithm or lookup table that takes in the analyte concentration and the cell-free hemoglobin concentration as inputs and outputs the cell-free hemoglobin interference threshold as a real number (the sample space having the number of possible outcomes is at least 3, e.g., at least 10, e.g., at least 100, e.g., at least 1000).

[0024] The predefined instructions may be set such that the relationship between the cell-free hemoglobin interference critical and both the (measured) analyte concentration and the (measured) cell-free hemoglobin concentration is non-stationary, such as non-linear. The predefined instructions may be set such that the cell-free hemoglobin interference critical cfHbic is given or can be described by a function cfHbic=f(cA, ccfHb) that depends on the analyte concentration cA and the cell-free hemoglobin concentration ccfHb, and the one or more contours of the function f(cA, ccfHb) are non-linear.

[0025] The predefined instructions may reflect or incorporate a particular categorization or parameterization of analyte concentrations relative to parameters and one or more rules based on which to determine the cell-free hemoglobin interference threshold. For example, the predefined instructions may be based on categorization of analyte concentrations into N categories according to several parameter categories, e.g., parameter values ​​{1, . . . , N}, and the rules for determining the cell-free hemoglobin interference threshold may state, for example, that the effect of cell-free hemoglobin interference is estimated, and the estimated cell-free hemoglobin interference may change a categorization based directly on measurements on a liquid sample by at least two categories, compared to a categorization based on a true analyte concentration, such as a measurement on a liquid sample, based on a measured analyte concentration and the estimated cell-free hemoglobin interference.

[0026] The categorization or parameterization may be according to clinical assessment, such as categorization into categories ranked according to morbidity and / or mortality. The rules (on which the instructions are based) may serve to reduce the risk of misdiagnosis, particularly in a direction that increases the risk of miscategorization (e.g., particularly relevant cases where miscategorization erroneously indicates morbidity and / or mortality as lower than it actually is), based on a particular measured analyte concentration and a particular cell-free hemoglobin concentration.

[0027] By 'automatically determining the cell-free hemoglobin interference threshold' it is understood that the device is capable of measuring the analyte concentration and the cell-free hemoglobin concentration in a liquid sample automatically - e.g., without human intervention after providing the liquid sample to the device - taking the analyte concentration and the cell-free hemoglobin concentration as input (and possibly having, accessing or otherwise taking other information as input, such as pre-defined instructions) and providing the cell-free hemoglobin interference threshold as output.

[0028] A 'sensor' is understood as commonly used in the art and may be, for example, an ion-selective electrochemical sensor, such as a potentiometric sensor. By 'measuring the concentration' it should be understood that the concentration is determined quantitatively, such as determining the molar concentration.

[0029] A 'data processing device' is understood as it is common in the art, and in particular as any device capable of receiving, processing and outputting digital information.

[0030] A 'processor' is understood as is common in the art, and in particular as an electronic circuit capable of executing instructions that constitute a computer program, for example a processing unit such as a central processing unit (CPU).

[0031] It is understood that by having a data processing device arranged to determine the cell-free hemoglobin interference threshold based on the cell-free hemoglobin concentration and the analyte concentration, the cell-free hemoglobin interference threshold may change value with a change in the value of either of the two concentrations, at least for one or more values ​​of the other concentration.

[0032] 'Outputting a signal' is understood as common in the art, such as providing externally to a data processing device information indicative of the acellular hemoglobin interference threshold. The output and signal format may take different forms, for example, as a digital or analog signal. For example, the signal output may be digital information representing the acellular hemoglobin interference threshold in a quantitative or qualitative form. In another example, the signal output is a visual and / or audible signal.

[0033] By outputting a signal 'at least if the acellular hemoglobin interference threshold is within a predefined range' it may be understood that a signal may be output in some embodiments regardless of the value of the acellular hemoglobin interference threshold. In other embodiments, a signal is output only if the acellular hemoglobin interference threshold is within a predefined range, e.g. 'high' or 'above 50', alternatively 'low' or 'below 50'. Thus, it is encompassed that a signal is output regardless of the value of the acellular hemoglobin interference threshold, that a signal is output only for acellular hemoglobin thresholds above a particular cutoff value (e.g., simply informing or flagging or suggesting retesting if the acellular hemoglobin threshold is high), or that a signal is output only for acellular hemoglobin thresholds below a particular cutoff value (e.g., simply informing the user if the acellular hemoglobin threshold is low).

[0034] Decisions (assistance) or suggestions (based on the measured concentration) as to whether or not to use (disclose) a measured analyte concentration, or not to use it (and retest instead), can be effectively decided / taken in advance, e.g., centrally, e.g., by qualified personnel with sufficient time, rather than relying on possibly less qualified personnel with perhaps very little time to make the right decision.

[0035] In one embodiment, a device is presented, which is arranged to receive a liquid sample in the form of a whole blood sample containing red blood cells at a sample inlet, e.g. a single sample inlet, and to measure at least the acellular hemoglobin concentration in at least a portion of the liquid sample that contains red blood cells or is in liquid communication with the red blood cells. For example, the device comprises a sample inlet, e.g. exclusively a single sample inlet, arranged to receive a whole blood sample and (micro)fluidically handle the sample to a measurement setting(s) / sensor(s) for measuring both the analyte concentration and the acellular hemoglobin concentration, e.g. both concentrations are determined for the same (portion) of the liquid sample, i.e. the portion in the liquid sample where the analyte concentration is determined is the same as or in fluid communication with the portion where the acellular hemoglobin concentration is determined. The advantage of this is that only a single liquid sample is needed, and / or Or only a single sample inlet may be required. Furthermore, it may be advantageous that the sample does not need to be divided into separate portions that are not in fluid connection, which may be beneficial in reducing requirements in both space and time, for example, there is no need to distance portions of the sample that are not in fluid connection with each other and / or there is no need to spend time on (liquid) separation of different portions of the sample. Furthermore, devices such as (micro)fluid handling may be made simpler. In one embodiment, the problem of red blood cells affecting the measurement of cell-free hemoglobin concentration in a liquid sample is solved by measuring a portion of the sample that is located within the pores of the porous element, for example by diffusion and / or capillary forces.

[0036] In one embodiment, a device is presented that is further arranged to measure at least an analyte concentration in at least the same portion of the liquid sample in which the cell-free hemoglobin concentration was measured, and / or in a portion of the sample that is in liquid communication with at least the portion of the liquid sample in which the cell-free hemoglobin concentration was measured. This can be advantageous in reducing complexity, as well as space and time requirements (see above).

[0037] In one embodiment, a device is provided that is arranged to measure an analyte concentration in a liquid sample and acellular hemoglobin concentration in a liquid sample at a spatial position less than 1 m, such as less than 75 cm, such as less than 50 cm, such as less than 25 cm, such as less than 10 cm, such as less than 1 cm from each other, for example, the maximum dimension of the device is 2 m or less, such as 1 m or less, such as 75 cm or less. The advantage of this is that a relatively small device may enable applications that would otherwise be impractical, such as point-of-care (POC) applications, and / or applications in which the device would be moved, for example, suddenly or by a person during the measurement. The relatively small size may allow the device(s) to be provided closer to the patient, which may reduce the time and generally the effect on the blood sample taken from the patient before it is provided to the device and subjected to measurement, which may allow more precise results (e.g., because the blood sample has changed less away from the true value).

[0038] In one embodiment, a device is presented that is arranged to receive at a first time point t1 a liquid sample in the form of a whole blood sample containing red blood cells at a sample inlet, and to output at a second time point t2 a signal indicating the acellular hemoglobin interference threshold if at least the acellular hemoglobin interference threshold is within a predetermined range, the time period between the first time point and the second time point being 10 minutes or less, for example 5 minutes or less, for example 2 minutes or less, for example 1 minute or less, for example 45 seconds or less, for example 35 seconds or less, for example 30 seconds or less, for example 10 seconds. The advantage of this may be that the device allows the device to save valuable time. Another possible advantage is that reducing the time, and therefore the impact on the sample that is generally taken from the patient before the blood sample is subjected to measurement, may allow for more precise results (e.g., because the blood sample, e.g., its measurable value, has not changed much relative to the true value).

[0039] In one embodiment, an apparatus is presented that further comprises a porous element, such as a porous mirror, and is configured to measure at least acellular hemoglobin concentration in a portion of the liquid sample positioned within one or more pores of the porous element.

[0040] According to one embodiment, the device comprises an optical measurement setup, e.g. comprising a porous mirror (PM), arranged to measure the cell-free hemoglobin concentration in a liquid sample, and / or an electroanalytical measurement setup, e.g. an ion selective electrode sensor, e.g. an ion selective electrode membrane sensor, for measuring an analyte concentration (analyte concentration may generally be understood to be the analyte concentration in the extracellular phase).

[0041] In one embodiment, the analyte concentration is K + For example, in blood samples, deviations from a predefined range can be associated with significant morbidity and mortality, and therefore it may be advantageous to obtain the concentration of potassium ions, and even acellular hemoglobin interference risk thresholds, for example, to aid in decisions regarding how to react to measured potassium ion concentrations.

[0042] In one embodiment, an apparatus, comprising: a data processing device; determining a cell-free hemoglobin interference threshold based on the analyte concentration; determining an cell-free hemoglobin interference value based on the cell-free hemoglobin concentration; comparing the cell-free hemoglobin interference value to a cell-free hemoglobin interference threshold; Determining cell-free hemoglobin interference thresholds based on the results of the comparison An apparatus is presented that is configured to determine cell-free hemoglobin interference thresholds by:

[0043] A possible advantage of determining and comparing based on a cell-free hemoglobin interference threshold value may be that it takes into account actual and / or estimated interference values, such as actual and / or estimated effects on analyte concentrations, which may be seen as the most relevant parameters.

[0044] In one embodiment, an apparatus is presented in which the cell-free hemoglobin interference threshold based on analyte concentration is an absolute value, e.g., the function describing the cell-free hemoglobin interference threshold as a function of analyte concentration is non-linear. A possible advantage of using an absolute value may be that it is relatively simple. A possible advantage of having the function that is non-linear may be that it allows for more accurate adjustment to clinically relevant images.

[0045] In one embodiment, an apparatus is presented in which the cell-free hemoglobin interference threshold based on analyte concentration is a relative value relative to the analyte concentration, e.g., the function describing the cell-free hemoglobin interference threshold as a function of analyte concentration is non-stationary, such as non-linear. A possible advantage of using a relative value is that it may allow for taking into account the analyte concentration, such as scaling to the analyte concentration, in a relatively simple manner. A possible advantage of having the function be non-stationary, such as non-linear, may be that it may allow for more accurate adjustment to a clinically relevant image.

[0046] In one embodiment, the data processing device comprises: determining a cell-free hemoglobin concentration threshold based on the analyte concentration; comparing the cell-free hemoglobin concentration or a parameter based on the cell-free hemoglobin concentration, such as the cell-free hemoglobin interference, to a cell-free hemoglobin concentration threshold; and Determining cell-free hemoglobin interference thresholds based on the results of the comparison The method is configured to determine the cell-free hemoglobin interference threshold by:

[0047] This embodiment may be advantageous due to the simplicity offered by having a threshold value. For example, according to a predefined instruction, each analyte concentration may be associated with a tolerance for a parameter based on acellular hemoglobin or acellular hemoglobin concentration (e.g., corresponding to a tolerable amount of acellular hemoglobin or acellular hemoglobin interference), which may be implemented in the data processing device as a threshold value for acellular hemoglobin and / or acellular hemoglobin interference, such as a non-stationary and optionally non-linear threshold value, which may be compared with the acellular hemoglobin concentration or acellular hemoglobin interference to provide acellular hemoglobin interference threshold based on this comparison, for example, according to one option, "above" or "below", or according to another option, a threshold value and acellular hemoglobin concentration or interference, which may be implemented in the data processing device as a non-stationary and optionally non-linear threshold value for acellular hemoglobin and / or acellular hemoglobin interference, such as a non-stationary and optionally non-linear threshold value, which may be compared with the acellular hemoglobin concentration or interference to provide acellular hemoglobin interference threshold based on this comparison, for example, according to one option, "above" or "below", or according to another option, a threshold value and acellular hemoglobin concentration or interference, which may be implemented in the data processing device as a non-stationary and optionally non-linear threshold value for acellular hemoglobin and / or interference, such as a non-stationary and optionally non-linear threshold value for acellular hemoglobin and / or interference, which may be implemented in the data processing device ... or a parameter based on cell-free hemoglobin concentration.

[0048] A possible advantage of determining and comparing based on a cell-free hemoglobin concentration threshold value may be that it is relatively simple, such as not requiring an estimation of interference values.

[0049] The 'cell-free hemoglobin concentration threshold' may be expressed as a relative or absolute (such as using the same units or quantity per unit as ccfHb or analyte concentration) value, where the relative value may be expressed as a function of the concentration of the analyte.

[0050] The cell-free hemoglobin concentration threshold may be expressed as a fraction or percentage of the analyte concentration and may be non-linear or linear, eg, constant or non-constant, eg, directly proportional or offset, with respect to the analyte concentration.

[0051] In one embodiment, an apparatus is presented in which the cell-free hemoglobin concentration threshold based on analyte concentration is a relative value that is relative to the analyte concentration, e.g., the function describing the cell-free hemoglobin concentration threshold as a function of analyte concentration is non-stationary, such as non-linear. A possible advantage of using a relative value is that it may allow for taking into account the analyte concentration, such as scaling against the analyte concentration, in a relatively simple manner. A possible advantage of having the function that is non-stationary, such as non-linear, may be that it may allow for more accurate adjustment to a clinically relevant image.

[0052] Alternatively, the cell-free hemoglobin concentration threshold may be expressed absolutely and may be non-linear or linear, eg, constant or non-constant, eg, directly proportional or offset, with respect to the analyte concentration.

[0053] In one embodiment, an apparatus is presented in which the cell-free hemoglobin concentration threshold based on analyte concentration is an absolute value, e.g., the function describing the cell-free hemoglobin concentration threshold as a function of analyte concentration is non-linear. A possible advantage of using an absolute value may be that it is relatively simple. A possible advantage of having the function that is non-linear may be that it allows for more accurate adjustment to a clinically relevant image.

[0054] The cell-free hemoglobin concentration threshold may be determined based on (1) literature values ​​for hemolysis detection and / or (2) a model relating analyte concentrations to parameters (such as a model that attributes specific clinical pictures to ranges of analyte concentrations) using rules that, for example, allow for interferences to move the categorization of a liquid sample across a boundary from one category to another, but do not allow interferences to bypass a category (i.e., move across an entire category / two boundaries).

[0055] In a further embodiment, a device is presented in which the cell-free hemoglobin threshold is a function of analyte concentration, the function varies numerically as analyte concentration increases within at least one analyte concentration interval, e.g., strictly increases within at least one analyte concentration interval having a range greater than zero (e.g., excluding functions that are non-stationary exclusively due to differences in values ​​between piecewise constant segments, e.g., excluding (Heaviside) step functions), the result of the function is non-stationary with respect to analyte concentration, e.g., increases as analyte concentration increases, or decreases as analyte concentration increases. In an embodiment, the function is neither strictly increasing nor strictly decreasing (e.g., has one or more local minima and / or one or more local maxima).

[0056] By having a non-stationary relationship between the cell-free hemoglobin threshold and the analyte concentration, it can be taken into account that a particular (relatively high) cell-free hemoglobin concentration is not necessarily significant or detrimental (for subsequent use, such as for subsequent decision making) for all analyte concentrations, while at the same time, another particular (relatively low) cell-free hemoglobin concentration may be significant or detrimental (for subsequent use, such as for subsequent decision making) for some analyte concentrations.

[0057] 'The cell-free hemoglobin threshold is a function of the analyte concentration' is understood to suggest that the cell-free hemoglobin threshold (for a given analyte concentration) can be determined as a function of the analyte concentration (or via a threshold function).

[0058] In another further embodiment, a device is presented in which the cell-free hemoglobin threshold is a function of analyte concentration, the function varying numerically as analyte concentration increases within at least one analyte concentration interval, e.g., strictly increasing within at least one analyte concentration interval having a range greater than zero, the result of the function being non-linear with respect to analyte concentration, e.g., increasing as analyte concentration increases, or decreasing as analyte concentration increases. By having a non-linear relationship between the cell-free hemoglobin threshold and the analyte concentration, more complex (e.g., non-linear) situations can be taken into account, such as more complex (e.g., non-linear) relationships between the parameter and the analyte concentration.

[0059] For example, a predefined effect on the parameter (determined by the measured analyte concentration) of an error in analyte concentration (due to the measured analyte concentration deviating from the true analyte concentration as a result of acellular hemoglobin interference) may be tolerated. By having a non-linear relationship between the threshold and the analyte concentration, it is possible to take into account the non-linear relationship between the parameter and the analyte concentration (and still be able to determine the acellular hemoglobin interference threshold according to a tolerance level across the analyte concentrations). This may be considered very beneficial, for example, with a view to not determining a too high critical value in a situation where the parameter does not change much due to (interference) errors, or to not determine a too low critical value in a situation where the parameter changes significantly due to (interference) errors of the same size.

[0060] The advantages discussed above for non-stationary and non-linear thresholds apply mutatis mutandis to non-threshold embodiments as well. According to one embodiment, the data processing device is operably connected to a storage device, the storage device comprising: a predefined categorization scheme, e.g., allowing for categorization of the liquid sample based on analyte concentrations (e.g., into a particular clinical presentation); The data processing device Determining a measured category of the liquid sample based on the analyte concentration, such as attributing the analyte concentration to a particular measured clinical picture (e.g., the (raw) measured analyte concentration is not adjusted for the interfering effects of cell-free hemoglobin); determining an adjusted concentration, such as an adjusted analyte concentration, where the adjusted concentration is based on an analyte concentration, such as a (raw) measured analyte concentration adjusted for interfering effects of cell-free hemoglobin, where the interfering effects of cell-free hemoglobin are based on the cell-free hemoglobin concentration; determining an adjusted category of the liquid sample based on the adjusted concentration, such as attributing the analyte concentration to an adjusted specific clinical picture; and Determining cell-free hemoglobin interference thresholds based on the degree of difference between measured and adjusted categories The method is configured to determine the cell-free hemoglobin interference threshold by:

[0061] An advantage may be that it allows for the utilisation of predefined categorisation schemes, such as clinical categorisation schemes where different ranges of analyte concentrations entail attribution to particular clinical pictures, such as 'life-threatening hypokalemia', 'severe hypokalemia', 'moderate hypokalemia', 'normal', 'moderate hyperkalemia', 'severe hyperkalemia' and 'life-threatening hyperkalemia'.

[0062] According to a further embodiment, the apparatus is configured such that the acellular hemoglobin interference threshold is either low or high, and the predefined categorization scheme is one-dimensional and includes at least three categories, and the acellular hemoglobin interference threshold is either low or high. Low, when the measured and adjusted categories are identical or adjacent within a given categorization scheme; If the measured category and the adjusted category are separated by at least one category within the predefined categorization scheme, a high (e.g., at least one category exists between the measured category and the adjusted category) device is presented.

[0063] This embodiment may be advantageous due to the simplicity it offers: in the formulation of the alternatives, the step from the measured category to the adjusted category is allowed to cross from one category to another, but the step is not allowed to bypass a category.

[0064] According to one embodiment, the data processing device is configured to output a signal conditional on the acellular hemoglobin interference threshold exceeding the acellular hemoglobin interference threshold. A possible advantage of this embodiment is that the user is only notified (or disturbed) if there is reason to be concerned about the acellular hemoglobin interference threshold.

[0065] According to another embodiment, the data processing device is configured to output a signal without qualification of the value of the acellular hemoglobin interference threshold. A possible advantage of this may be that the user may be (explicitly) informed about the acellular hemoglobin interference threshold.

[0066] According to one embodiment, the analyte concentration is determined by: K + Ions such as potassium ions, Sodium ions, such as Na+ ions, Ca 2+ Ions such as calcium ions, glucose, Creatinine, and Lactic acid is the concentration of the analyte selected from the group consisting of:

[0067] The advantage of this is that any one of the listed analytes may be relevant to human health, and thus each of their concentrations (e.g., in a blood sample) and the cell-free hemoglobin interference threshold may be relevant to the assessment of human health.

[0068] According to one embodiment, the device according to any of the preceding claims, wherein the analyte concentrations are a plurality of analyte concentrations of the analytes, for at least two of the analytes: The data processing device Cell-free hemoglobin interference criticality, Cell-free hemoglobin concentration, and Analyte concentration Based on the decision, configured to output a signal indicative of the acellular hemoglobin interference threshold at least when the acellular hemoglobin interference threshold is within a predetermined range; An apparatus is presented in which the relationship between the cell-free hemoglobin interference threshold and the analyte concentration is unique for at least two analytes, and thus different for each analyte.

[0069] An advantage may be that a signal indicating cell-free hemoglobin interference thresholds may be output for multiple ions (such as to warn a possibly non-expert user that interference is or may be significant). Another possible advantage may be that it may be taken into account that different analytes may be affected differently by cell-free hemoglobin (see also our data in Tables I-II, which reveal that measurements of different analyte concentrations may be affected / interfered with differently for a particular ccfHb compared to measurements of concentrations of other analytes) and / or that the attribution of analyte concentrations to a particular clinical picture may be different for different analytes (e.g., even in the case of a particular level of interference at a particular concentration of each of two analytes, the cfHb interference threshold may be different due to the risk that the interference may change the attribution to a particular clinical picture based on the concentration to a greater extent for one analyte compared to the other analyte). According to one embodiment, the cell-free hemoglobin interference threshold is determined for at least two analytes by calculating the cell-free hemoglobin interference effect for each analyte (i.e., the absolute quantitative effect that the interference has on each analyte, which may vary from analyte to analyte), and the apparatus is arranged such that interference effects of similar size may result in different cell-free hemoglobin interference thresholds, even when each of the at least two analytes has the same concentration.

[0070] According to one embodiment, a device is presented that further comprises a user interface, such as a graphic user interface, arranged to visually output information representative of the signal. A possible advantage of this may be that the user can visually observe the information representative of the signal. Another possible advantage is that the content of the information, for example the acellular hemoglobin interference threshold value (such as '45.876') and / or a guide on how to proceed (such as 'acellular hemoglobin interference threshold exceeds acceptable value - please retest'), may be presented to a user, including a non-expert user, allowing the user to obtain the relevant information very quickly (e.g. compared to outputting the corresponding information audibly or digitally).

[0071] According to one embodiment, an apparatus is provided, comprising: and a user interface, such as a graphical user interface, arranged to receive user input, such as an acellular hemoglobin concentration threshold for a particular analyte concentration; The data processing device An apparatus is presented that is configured to determine an acellular hemoglobin interference threshold based on user input.

[0072] A possible advantage may be that a user can provide user input, e.g., predetermined instructions, or simply cell-free hemoglobin concentration thresholds for particular analyte concentrations, and the data processing device can then take this into account, e.g., by providing non-stationary cell-free hemoglobin concentration thresholds according to the predetermined instructions or including the provided cell-free hemoglobin concentration thresholds for particular analyte concentrations. Thus, a user can provide or influence pre-defined instructions on how the cell-free hemoglobin critical is determined, optionally in a semi-automated manner. For example, a laboratory or point-of-care administrator can provide a predetermined instruction on how a ... + ) to select an acceptable detection limit, where the threshold is K + All Analysis The concentration of the substance is determined automatically.

[0073] According to one embodiment, an apparatus is presented, in which the cell-free hemoglobin interference threshold is determined based on a function, such as a look-up table, or an algorithm, or a mathematical function.

[0074] According to one embodiment, an apparatus is provided, comprising: for at least one first analyte concentration, the first change in the cell-free hemoglobin interference threshold changes with increasing cell-free hemoglobin concentration at the first cell-free hemoglobin concentration; for at least one second analyte concentration, the second change in the cell-free hemoglobin interference threshold changes with increasing cell-free hemoglobin concentration at the second cell-free hemoglobin concentration; the first change is substantially the same as, or identical to, the second change, such that the first change and the second change each correspond to exceeding an acellular hemoglobin threshold; the first analyte concentration is less than the second analyte concentration; and Apparatuses are presented in which the first cell-free hemoglobin concentration is different from the second cell-free hemoglobin concentration, such as being less than or greater than the second cell-free hemoglobin concentration.

[0075] An advantage of this embodiment may be that the change in cell-free hemoglobin criticality is not limited to occurring at a constant analyte concentration. According to one embodiment, the device comprises: Apparatuses are presented in which the cell-free hemoglobin threshold based on the lower of two different analyte concentrations is different, such as less than or greater than, the cell-free hemoglobin threshold based on the higher of two different analyte concentrations.

[0076] An advantage of this embodiment is that the cell-free hemoglobin threshold is not limited to being a constant with respect to analyte concentration. According to one embodiment, the device, for example a blood gas analyzer, comprises: Carbon dioxide, e.g. CO2, Oxygen, e.g., O2, and pH in a liquid sample.

[0077] An advantage of having such a (blood gas analyzer) device may be that it makes it possible to provide further relevant liquid (blood) sample parameters, e.g. via an output a (non-expert) user (even) may be informed whether e.g. one or more analytes may be associated with a high (too high) cell-free hemoglobin interference threshold, that retesting may be necessary, etc. The advantage is, for example, that it offers a fast response time, a relevant output to a non-expert user, and a relevant solution for point-of-care testing, where one or more or all of the multiple parameters may be particularly relevant.

[0078] According to a second aspect of the present invention, there is provided a method for automatically measuring an analyte concentration in a liquid sample comprising an analyte and acellular hemoglobin, and for automatically determining an acellular hemoglobin interference threshold, comprising the steps of: a. determining an analyte concentration in a liquid sample; b. measuring the cell-free hemoglobin concentration in the liquid sample; c. a data processing device having a processor, analyte concentration, Cell-free hemoglobin concentration providing a d. Using a data processing device, Cell-free hemoglobin concentration, and Analyte concentration and automatically determining an acellular hemoglobin interference threshold based on the e. outputting a signal indicative of the acellular hemoglobin interference threshold from the data processing device at least if the acellular hemoglobin interference threshold is within the predetermined range; A method is presented that includes:

[0079] In one embodiment, the method comprises determining the cell-free hemoglobin interference threshold by: a. further based on a predefined categorization scheme, for example, the predefined categorization scheme allows for categorizing the liquid sample based on analyte concentration; The method comprises: b. determining a measured category of the liquid sample based on the analyte concentration, such as attributing the analyte concentration to a particular measured clinical picture; c. determining an adjusted concentration, such as an adjusted analyte concentration, where the adjusted concentration is based on an analyte concentration, such as a measured analyte concentration adjusted for interfering effects of acellular hemoglobin, where the interfering effects of acellular hemoglobin are based on the acellular hemoglobin concentration; d. determining an adjusted category of the liquid sample based on the adjusted concentration, such as attributing the analyte concentration to an adjusted specific clinical picture; and e. determining a cell-free hemoglobin interference threshold based on the degree of difference between the measured category and the adjusted category; A method is presented that includes determining a cell-free hemoglobin interference threshold by:

[0080] In one embodiment, the method comprises the steps of: Samples containing cells such as red blood cells, a sample derived from a sample containing cells such as red blood cells; a whole blood sample, such as a human whole blood sample, or Methods are presented in which the sample is derived from a whole blood sample such as serum or plasma, e.g., derived from a human whole blood sample, such as being a diluted whole blood sample and / or being a fraction of a human whole blood sample.

[0081] An advantage of this embodiment is that hemolysis may have occurred, which may have caused interference (e.g., by releasing potassium ions into the liquid sample after withdrawal from the patient), and this may be addressed by determining the cell-free hemoglobin interference threshold.

[0082] In one embodiment, a method, when the cell-free hemoglobin threshold exceeds the cell-free hemoglobin interference threshold, the method further comprises: obtaining another liquid sample containing the analyte and cell-free hemoglobin and repeating steps a through e. A method is presented, further comprising:

[0083] A possible advantage may be that determining the acellular hemoglobin interference threshold may trigger certain actions, which may result in the acellular hemoglobin interference threshold not exceeding the acellular hemoglobin interference threshold.

[0084] According to a third aspect of the present invention there is provided a computer program, such as a computer program product, which when executed by a computer comprises: receiving first information based on an analyte concentration; receiving second information based on the cell-free hemoglobin concentration; Cell-free hemoglobin interference criticality, Cell-free hemoglobin concentration, and Analyte concentration to make a decision based on outputting a signal indicative of the acellular hemoglobin interference threshold at least when the acellular hemoglobin interference threshold is within a predetermined range; A computer program is presented that includes instructions for causing a computer to:

[0085] According to another aspect, a computer readable data carrier is presented having stored thereon the computer program of the third aspect. According to another aspect, a data processing apparatus is presented, comprising a processor adapted to perform the method of the second aspect and / or adapted to execute a computer program according to the third aspect.

[0086] According to another aspect, there is provided a method for providing predefined instructions, e.g. a device and / or a computer program based on said predefined instructions, comprising: Obtaining a predefined categorization scheme, for example, the predefined categorization scheme allowing for categorizing the liquid sample based on analyte concentration; For each assumed pair or analyte concentration and cell-free hemoglobin concentration: determining a measured category of the liquid sample based on the analyte concentration, such as attributing the analyte concentration to a particular measured clinical picture; determining an adjusted concentration, such as an adjusted analyte concentration, where the adjusted concentration is based on an analyte concentration, such as a measured analyte concentration, adjusted for interfering effects of acellular hemoglobin, where the interfering effects of acellular hemoglobin are based on the acellular hemoglobin concentration; determining an adjusted category of the liquid sample based on the adjusted concentration, such as attributing the analyte concentration to an adjusted specific clinical picture; determining a cell-free hemoglobin interference threshold based on the degree of difference between the measured category and the adjusted category; providing predetermined instructions, such as a look-up table or algorithm, as a set of data that links each assumed pair of analyte concentration and cell-free hemoglobin concentration with the determined cell-free hemoglobin interference threshold. determining a cell-free hemoglobin interference threshold by A method is presented, including:

[0087] In the context of point-of-care measurement systems (also referred to in the art as 'bed-site' systems) and similar laboratory environments, blood gas analysis is often performed by users, such as nurses, who may not be trained users in the use of blood gas analyzers and / or interpretation of results. This can lead to unnecessary retesting (e.g. due to a user being overly cautious about samples where interference may be an issue, even when a correct interpretation would have revealed that retesting was not necessary), or erroneous reliance on a result (e.g. a result that should not have been relied on due to the risk of misdiagnosis due to interference) in situations where a correct interpretation would have led to not relying on the result.

[0088] According to another aspect of the present invention, Cell-free hemoglobin interference criticality, Cell-free hemoglobin concentration, and Analyte concentration Based on the decision, and outputting a signal indicative of the acellular hemoglobin interference threshold at least if the acellular hemoglobin interference threshold is within a predetermined range. The use of the device according to the second aspect of the invention for point-of-care (POC) use is presented.

[0089] POC measurements are also referred to in the art as 'bed-site' measurements. In this context, the term 'point-of-care measurements' should be understood to mean measurements performed close to the patient, i.e. not in a laboratory. Thus, according to this embodiment, a user of a device such as a blood gas analyzer performs the measurement of a whole blood sample in a handheld blood sample container close to the patient from whom the blood sample is taken, for example in the room or ward housing the patient's bed, or in a nearby room in the same department. In such applications, the level of expertise of the users often varies from novice to expert, and therefore the ability of the blood gas analyzer to automatically output instructions based on sensor inputs that match the skills of each individual user is particularly beneficial in such environments.

[0090] According to an alternative third aspect, there is presented a computer program, such as a computer program product, comprising instructions for causing an apparatus according to the first aspect to perform the steps of the method of the second aspect.

[0091] According to a further aspect, a computer readable medium having stored thereon the computer program of the third aspect and / or the computer program of an alternative third aspect is presented.

[0092] Each of the first, second and third aspects of the invention may be combined with any of the other aspects. These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter.

[0093] An apparatus, method, and computer program product for automatically measuring an analyte concentration in a liquid sample containing cell-free hemoglobin, according to the present invention, will now be described in more detail with reference to the accompanying drawings, which illustrate one way of implementing the invention and should not be construed as limiting to other possible embodiments falling within the scope of the appended claim set. [Brief description of the drawings]

[0094] [Figure 1] FIG. 1 is a schematic diagram of an apparatus 100 for automatically determining an analyte concentration in a liquid sample. [Diagram 2] FIG. 1 illustrates an example of cell free hemoglobin concentration (ccfHb) thresholds according to predefined instructions, according to one embodiment. [Diagram 3] FIG. 13 illustrates another example of cell free hemoglobin concentration (ccfHb) thresholds according to predefined instructions, according to one embodiment. [Figure 4] FIG. 13 illustrates another example of cell free hemoglobin concentration (ccfHb) thresholds according to predefined instructions, according to one embodiment. [Diagram 5] FIG. 2 illustrates a wireframe 3D surface of a function according to one embodiment. [Figure 6]FIG. 6 shows a wireframe contour plot of the function also depicted in FIG. 5. [Figure 7] FIG. 7 illustrates a method 700 for automatically determining an analyte concentration in a liquid sample 102. [Figure 8] FIG. 1 shows fixed and non-stationary cell-free hemoglobin (interference) thresholds according to Example 1. [Figure 9] FIG. 1 shows fixed and non-stationary cell-free hemoglobin (interference) thresholds according to Example 2. [Figure 10] FIG. 13 shows fixed and non-stationary cell-free hemoglobin (interference) thresholds according to Example 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0095] FIG. 1 is a schematic diagram of an apparatus 100 for automatically measuring an analyte concentration in a liquid sample 102 containing an analyte and cell-free hemoglobin, and for automatically determining a cell-free hemoglobin interference threshold, the apparatus comprising: One or more sensors 104, the analyte concentration in the liquid sample, and one or more sensors 104 for measuring the cell-free hemoglobin concentration in the liquid sample; A data processing device 106 comprising a processor, Cell-free hemoglobin interference criticality, Cell-free hemoglobin concentration, and Analyte concentration Based on the decision, a data processing device 106 configured to output a signal 108 indicative of the acellular hemoglobin interference threshold at least if the acellular hemoglobin interference threshold is within a predetermined range; Equipped with.

[0096] In the depicted embodiment, the one or more sensors 104 include two sensors for measuring an analyte concentration in the liquid sample and an acellular hemoglobin concentration in the liquid sample, respectively. The schematic diagram of Fig. 1 further shows a liquid sample inlet 112, a microfluidic system 114, a storage device 116, a user interface 118, which comprises an output unit 120 arranged to visually output information representative of a signal (the output unit in the depicted embodiment is a display unit depicting a signal 108 indicating to a user that the acellular hemoglobin interference threshold exceeds an acceptable value and a warning against proceeding with the measured analyte concentration is issued), and an input unit 122 (such as a keyboard). The thin arrows indicate the flow of information, such as an analyte concentration in the liquid sample and acellular hemoglobin concentration in the liquid sample, flowing from one or more sensors 104 to the data processing device 106, output signals flowing from the data processing device 106 to the user interface 118 (and more particularly, the output unit 120), user input flowing from the input unit 122 to the data processing device 106 (which can be processed so that the data processing device can modify pre-defined instructions in the storage device 116), and pre-defined instructions flowing from the storage device 116 to the data processing device 106.

[0097] The one or more sensors 104 may comprise a porous element, such as a porous mirror, for example, to measure the concentration of acellular hemoglobin in a liquid sample. Briefly, porous mirror (PM) is a technology for providing absorbance measurements of the plasma phase of a whole blood (WB) sample. It can be used to determine the concentration of acellular hemoglobin (ccfHb). In an embodiment, it works by allowing ccfHb to diffuse into a porous PETP membrane that has a pore size smaller than red blood cells (RBCs). The RBCs are thus kept out from entering the pores. The pores are non-penetrating on the inside of the membrane, so that they are smaller than 1 mm. 2 Each of the 1.2 million holes per well constitutes a nanocuvette (φ=400 nm, length=25 mm) in close proximity to the sample. μm). ccfHb and other plasma components are transported in and out of the nanocuvette by diffusion. The front side of the porous membrane (facing the sample) is covered with a precious metal (Pd, thickness = 100 nm) but is still open at the pore ends facing the sample. The metal layer in front of the membrane allows light reflection (mirror in PM) that allows transmission-like measurement of hemoglobin (Hb) inside the pores from the back side of the membrane. Conveniently, optical interference from Hb in RBCs and / or other particulate matter in the sample is suppressed to negligible levels by the same optically shielding metal layer. The porous mirror device is a porous mirror for detection of analytes in liquids by optical probes, a light-transmitting slab having a front side and a back side facing away from the front side, the front side being adapted to contact a fluid; a reflective layer on the front side of the light-transmitting slab, the reflective layer adapted to reflect light reaching the reflective layer from the back side of the light-transmitting slab; Equipped with the optically transmissive slab includes holes, the holes being blind holes extending from respective openings in the front side, through the reflective layer, and into the optically transmissive slab; The pore openings may be porous mirrors, dimensioned to prevent larger particles or debris, if contained in the fluid, from entering the pores while allowing analytes in the fluid to enter the pores by diffusion. Porous mirror (PM) technology is described in WO2017 / 085162A1, which is incorporated herein by reference in its entirety, and is particularly described in claim 1 of WO2017 / 085162A1, as well as further in FIG. 1 and the accompanying text on pages 24-25.

[0098] FIG. 2 illustrates an example of a cell-free hemoglobin concentration (ccfHb) threshold according to a predetermined command, which is non-stationary and linear, and in particular, directly proportional to the analyte concentration (cA), according to one embodiment.

[0099] FIG. 3 shows another example of a cell-free hemoglobin concentration (ccfHb) threshold according to a predetermined command, in accordance with one embodiment, where the threshold is non-stationary and linear, and the threshold is defined by a proportionality constant k=ccfHb / cA with respect to the analyte concentration (cA) (even though it is not directly proportional).

[0100] 4 shows another example of a cell-free hemoglobin concentration (ccfHb) threshold according to a predetermined command according to one embodiment, where the threshold is non-stationary and non-linear, i.e., the threshold cannot be defined by a proportionality constant k=ccfHb / cA with respect to analyte concentration (cA). In the particular embodiment shown, the relationship between the threshold value and the analyte concentration is defined by a second order polynomial. In the particular embodiment shown, the threshold value is neither strictly increasing nor strictly decreasing with respect to the analyte concentration.

[0101] 5-6 relate to an embodiment in which the cell-free hemoglobin interference threshold is determined (qualified) on an interval or ratio scale, such as provided as a real number on a scale of 0 to 15. A function takes as arguments the analyte concentration (cA) and the cell-free hemoglobin concentration (ccfHb) and provides as a result the cell-free hemoglobin interference threshold (z).

[0102] 5 shows a wireframe 3D surface of a function according to an embodiment in which the cell-free hemoglobin interference threshold is determined (qualified) by the function as a value on an interval or ratio scale, such as a real number on a scale of 0 to 15. The function takes as arguments the analyte concentration (cA) and the cell-free hemoglobin concentration (ccfHb), and provides as a result the cell-free hemoglobin interference threshold (z).

[0103] FIG. 6 shows a wireframe contour plot of the function also depicted in FIG. 5, where the contour line 610 is non-linear (ie, not a straight line in the figure). FIG. 7 illustrates an automated method for determining an analyte concentration in a liquid sample 102 that contains an analyte and cell-free hemoglobin. FIG. 7 illustrates a method 700 for automatically determining cell-free hemoglobin interference thresholds, beginning at block 719, the method comprising: a. determining 720 an analyte concentration in the liquid sample; b. measuring 722 the cell-free hemoglobin concentration in the liquid sample; c. A data processing device 106 having a processor, analyte concentration, Cell-free hemoglobin concentration providing a d. Using a data processing device, Cell-free hemoglobin concentration, and Analyte concentration and automatically determining 724 the cell-free hemoglobin interference threshold based on e. outputting a signal indicating the acellular hemoglobin interference threshold from the data processing device if the acellular hemoglobin interference threshold is within the predetermined range; Includes.

[0104] FIG. 8 further shows step 718 of measuring the concentration, and step 728 of determining whether the cell-free hemoglobin threshold exceeds the cell-free hemoglobin interference threshold, and step 732 of obtaining another liquid sample containing the analyte and cell-free hemoglobin and repeating steps a-e (if the cell-free hemoglobin threshold exceeds the cell-free hemoglobin interference threshold), or step 730 of ending the method, such as by releasing the analyte concentration to a user (if the cell-free hemoglobin threshold is equal to or below the cell-free hemoglobin interference threshold).

[0105] In order to provide clinically relevant devices and methods (such as allowing to evaluate the clinically relevant impact of cell-free hemoglobin on clinically relevant measured analyte concentrations), it may be important to obtain (quantitative) data on the interference of cell-free hemoglobin with relevant analytes. Thus, an interference test table with an overview of the interference of cell-free hemoglobin with several analytes is provided in Table I below, said data being determined with respect to cell-free hemoglobin concentration (ccfHb).

[0106] [Table 1]

[0107] Furthermore, the interference was quantified (by 'correlation coefficient') by measurements on whole blood samples and the results are shown in Table II.

[0108] [Table 2]

[0109] From Table II, for potassium ion, the measured analyte concentration cA m It can be derived that the interference from cell-free hemoglobin can be estimated as the product of the correlation coefficient and the cell-free hemoglobin concentration, i.e., +0.3 mM / (100 mg / dL cfHb) × ccfHb (i.e., the interference has the effect of making the measured analyte concentration higher than the true analyte concentration, and as a result, the true analyte concentration cA t is cA t =cA m It can be estimated as −0.3 mM / (100 mg / dL cfHb) × ccfHb.

[0110] To provide a clinically relevant cell-free hemoglobin interference threshold, it may be important to translate clinically relevant information into the default order, for example with a view to being able to detect severe hypokalemia for samples with hemolysis and / or to be able to detect false hyperkalemia due to hemolysis. According to a simplified model, the clinical picture for potassium ion concentration is as follows (for non-neonatal patients): 1 <K + ≤2.5 mM Severe hypokalemia 2.5 <K + ≤3.5mM Mild hypokalemia 3.5 <K + ≦5mM normal 5 <K + ≦6mM Mild hyperkalemia ·K + >6 Severe hyperkalemia For newborns, the model is slightly different: 1 <K + ≤3.5 mM Severe hypokalemia 3.5 <K + ≤4.5mM Mild hypokalemia 4.5 <K + ≦6mM normal 6 <K + ≤7mM Mild hyperkalemia ·K + >7 Severe hyperkalemia The above ranges embody a categorization of analyte concentrations into categories that represent particular clinical manifestations, such as embodying a predefined categorization scheme.

[0111] According to an embodiment of the present invention (hereinafter, K + For example, the functions used may be different and the same type of model may be used in other models, such as Na + and Ca 2+ (note that the cell-free hemoglobin interference threshold can be used for + (instead of using the same cell-free hemoglobin concentration threshold at all levels of+ Lower in levels, normal K + and high K + The concentration is set higher. This can be determined by a threshold value that is used to determine the + This can result in high quality monitoring of levels and a low number of unwanted detections of hemolysis in the liquid sample.

[0112] It should be noted that samples from the neonatal region will have different reference levels (see below), but the concepts of the present invention can be applied using the same thresholds as for adult samples.

[0113] The following are the K values ​​for 1) clinically acceptable non-stationary levels at 0.3 mM for adult samples vs. analytically acceptable constant levels, 2) clinically acceptable non-stationary levels at 0.5 mM for adult samples vs. analytically acceptable constant levels, and 3) clinically acceptable non-stationary levels at 1.0 mM for neonatal samples vs. analytically acceptable constant levels. + An example of the concept of concentration-dependent hemolysis detection (which may be considered equivalent or identical to detection of cell-free hemoglobin exceeding a critical threshold) is provided. 'Analytical' is generally understood to mean directly dependent on concentration, rather than directly taking into account clinical considerations, and 'clinical' is generally understood to mean rather dependent on clinical considerations.

[0114] In the following examples, reference is made to 'true patient values' which are given under the assumption of in vitro hemolysis (because in the case of in vivo hemolysis the sample concentrations are also true patient values). EXAMPLES

[0115] Example 1: Safe detection of hypokalemia (set threshold: 0.3 mM): Three different patients were + Concentration, cA m ]=2.8 mM, 5.5 mM, and 6.3 mM were measured.

[0116] The measured [ccfHb] = 130 mg / dL and the set threshold: 0.3 mM (100 mg / dL). True patient value, cA t :K + Measured K for + influence, In the formula, K + Effect on Hb = 130 mg / dL × 0.3 mM / (100 mg / dL cfHb) = 0.39 mM.

[0117] [Table 3]

[0118] K + The dynamic maximum effect on is a value determined with due consideration of the underlying clinical picture(s) that results in the cell-free hemoglobin (interference) threshold being describable as a second order polynomial function versus analyte concentration as depicted in FIG. 8, where a fixed threshold at 0.3 mM is also shown.

[0119] It can be seen from this example that the non-constant threshold according to the present invention is advantageous because the analyte concentrations of the two samples are made public (samples that did not require retesting when demonstrated using a non-constant threshold), whereas retesting was required for fixed samples.

[0120] Example 2: Safe detection of hypokalemia (set threshold: 0.5 mM): Three different patients were + Concentration, cA m ]=2.9 mM, 5.0 mM, and 6.4 mM were measured.

[0121] The measured [ccfHb] = 151 mg / dL and the set threshold: 0.5 mM (165 mg / dL). True patient value, cAt:K + Measured K for + influence, In the formula, K +Effect on = 151 mg / dL × 0.3 mM / (100 mg / dL cfHb) = 0.45 mM.

[0122] [Table 4]

[0123] K + The dynamic maximum effect on is a value determined with due consideration of the underlying clinical picture(s) that results in the cell-free hemoglobin (interference) threshold being describable as a second order polynomial function versus analyte concentration as depicted in FIG. 9, where a fixed threshold at 0.5 mM is also shown.

[0124] It can be seen from this example that the non-constant threshold according to the present invention is advantageous because the analyte concentration of a sample is not disclosed, but instead requires retesting, as it was disclosed in the case of fixed samples (although retesting was required when demonstrated using a non-constant threshold). This is because, for example, with a fixed threshold, the measured K + Concentration cA m = 2.9 mM is publicly available, i.e., it may be provided to personnel who may categorize it as indicating mild hypokalemia. However, the estimated true patient K + According to the concentration (2.4 mM), the (true patient) categorization was in fact severe hypokalemia. However, using the (dynamic) threshold according to this embodiment of the invention, the cell-free hemoglobin interference threshold is assessed as unacceptably high and a retest is requested instead.

[0125] Example 3: Safe detection of hypokalemia (set threshold: 1.0 mM): Three different patients were + Concentration, cA m ]=3.8 mM, 4.5 mM, and 7.0 mM were measured.

[0126] The measured [ccfHb] = 290 mg / dL and the set threshold: 1.0 mM (330 mg / dL). True patient value, cA t :K + Measured K for + influence, In the formula, K + Effect on = 290 mg / dL × 0.3 mM / (100 mg / dL cfHb) = 0.87 mM.

[0127] [Table 5]

[0128] K + The dynamic maximum effect on is a value determined with due consideration of the underlying clinical picture(s) that results in the cell-free hemoglobin (interference) threshold being describable as a second order polynomial function versus analyte concentration as depicted in FIG. 10, where a fixed threshold at 0.5 mM is also shown.

[0129] It can be seen from this example that the non-constant threshold according to the present invention is advantageous because the analyte concentrations of the two samples are not disclosed, but instead require retesting, whereas in the case of the fixed sample it was disclosed (although retesting was required when demonstrated using a non-constant threshold).

[0130] Although the present invention has been described in relation to specific embodiments, it should not be construed as being limited in any way to the examples presented. The scope of the present invention is defined by the attached claim set. In the context of the claims, the term "comprising" or "comprises" does not exclude other possible elements or steps. Also, the description of a reference such as "a" or "an" should not be construed as excluding a plurality. The use of reference signs in the claims for elements shown in the figures should also not be construed as limiting the scope of the present invention. Moreover, individual features recited in different claims may possibly be advantageously combined, and the recitation of these features in different claims does not exclude that a combination of features is not possible and advantageous.

Claims

1. An apparatus (100) for automatically measuring the concentration of an analyte in a liquid sample (102) containing an analyte and cell-free hemoglobin, and for automatically determining a cell-free hemoglobin interference threshold, said apparatus comprising: one or more sensors (104), said concentration of the analyte in said liquid sample, and the concentration of cell-free hemoglobin in said liquid sample one or more sensors (104) for measuring; a data processing device (106) comprising a processor, said cell-free hemoglobin interference threshold, said concentration of cell-free hemoglobin, and said concentration of the analyte determined based on, a data processing device (106) configured to output a signal (108) indicating said cell-free hemoglobin interference threshold when at least said cell-free hemoglobin interference threshold is within a predetermined range; comprising, at least said concentration of the analyte is further arranged to be measured in at least the same portion of said liquid sample in which the concentration of cell-free hemoglobin is measured and / or in a portion of the sample that is in liquid connection with at least said portion of the liquid sample in which the concentration of cell-free hemoglobin is measured. Apparatus (100).

2. The apparatus (100) according to claim 1, arranged to receive said liquid sample in the form of a whole blood sample containing red blood cells at a sample inlet, for example a single sample inlet, and to measure at least said concentration of cell-free hemoglobin in at least a portion of said liquid sample containing or in liquid connection with said red blood cells.

3. Arranged to measure the concentration of the analyte in said liquid sample and the concentration of cell-free hemoglobin in said liquid sample at a spatial position less than 1 m, for example less than 75 cm, for example less than 50 cm, for example less than 25 cm, for example less than 10 cm, for example less than 1 cm from each other, for example, the maximum dimension of said apparatus is 2 m or less, for example 1 m or less, for example 75 cm or less. Apparatus (100) according to claim 1 or 2.

4. At the first time point t1, to receive the liquid sample in the form of a whole blood sample containing red blood cells at the sample inlet, and when at least the cell-free hemoglobin interference critical value is within a predetermined range, at the second time point t2, arranged to output a signal (108) indicating the cell-free hemoglobin interference critical value, and the time period between the first time point and the second time point is 10 minutes or less, for example 5 minutes or less, for example 2 minutes or less, for example 1 minute or less, for example 45 seconds or less, for example 35 seconds or less, for example 30 seconds or less, for example 10 seconds or less, the device (100) according to any one of claims 1 to 3.

5. Further comprising a porous element such as a porous mirror, and arranged to measure at least the cell-free hemoglobin concentration in a portion of the liquid sample positioned within one or more pores of the porous element, the device (100) according to any one of claims 1 to 4.

6. The analyte concentration is the concentration of potassium ions, the device (100) according to any one of claims 1 to 5.

7. The data processing device (106) determining a cell-free hemoglobin interference threshold based on the analyte concentration, determining a cell-free hemoglobin interference value based on the cell-free hemoglobin concentration, comparing the cell-free hemoglobin interference value with the cell-free hemoglobin interference threshold, and determining the cell-free hemoglobin interference critical value based on the result of the comparison Thereby, the device (100) according to any one of claims 1 to 6 is configured to determine the cell-free hemoglobin interference critical value.

8. The cell-free hemoglobin interference threshold based on the analyte concentration is an absolute value. For example, the function explaining the cell-free hemoglobin interference threshold as a function of the analyte concentration is non-linear, the device (100) according to claim 7.

9. The cell-free hemoglobin interference threshold based on the analyte concentration is a relative value relative to the analyte concentration. For example, the function explaining the cell-free hemoglobin interference threshold as a function of the analyte concentration is non-linear, such as non-steady, the device (100) according to claim 7.

10. The data processing device (106) determining a cell-free hemoglobin concentration threshold based on the analyte concentration, Comparing the cell-free hemoglobin concentration or a parameter based on the cell-free hemoglobin concentration with the cell-free hemoglobin concentration threshold, and determining the cell-free hemoglobin interference threshold based on the result of the comparison The apparatus (100) according to any one of claims 1 to 9, which is configured to determine the cell-free hemoglobin interference threshold by: **Claim 11** The cell-free hemoglobin concentration threshold based on the analyte concentration is an absolute value. For example, the function that describes the cell-free hemoglobin concentration threshold as a function of the analyte concentration is non-linear. The apparatus (100) according to claim 10. **Claim 12** The cell-free hemoglobin concentration threshold based on the analyte concentration is a relative value relative to the analyte concentration. For example, the function that describes the cell-free hemoglobin concentration threshold as a function of the analyte concentration is non-steady, such as non-linear. The apparatus (100) according to claim 10. **Claim 13** The cell-free hemoglobin threshold is a function of the analyte concentration, and the function numerically changes as the analyte concentration increases within at least one analyte concentration interval. For example, within at least one analyte concentration interval having a range greater than zero, it strictly increases. The result of the function, etc., increases as the analyte concentration increases, or decreases as the analyte concentration increases, etc., and is non-steady with respect to the analyte concentration. The apparatus (100) according to claim 10. **Claim 14** The cell-free hemoglobin threshold is a function of the analyte concentration, and the function numerically changes as the analyte concentration increases within at least one analyte concentration interval. For example, within at least one analyte concentration interval having a range greater than zero, it strictly increases. The result of the function, etc., increases as the analyte concentration increases, or decreases as the analyte concentration increases, etc., and is non-linear with respect to the analyte concentration. The apparatus (100) according to any one of claims 10 to 13. **Claim 15** The data processing device (106) is operably connected to a storage device (110), and the storage device comprises a predefined categorization scheme. For example, the predefined categorization scheme enables categorizing a liquid sample based on the analyte concentration. The data processing device (106) Determining the measured category of the liquid sample based on the analyte concentration, such as attributing the analyte concentration to a specific measured clinical picture. Determining an adjusted concentration, such as an adjusted analyte concentration, where the adjusted concentration is adjusted for the interference effect of the cell-free hemoglobin, based on the measured analyte concentration, etc., and the interference effect of the cell-free hemoglobin is based on the cell-free hemoglobin concentration, determining an adjusted concentration. Determining an adjusted category of the liquid sample based on the adjusted concentration, such as attributing the analyte concentration to an adjusted specific clinical picture, and Determining the cell-free hemoglobin interference threshold based on the degree of difference between the measured category and the adjusted category. The apparatus (100) according to any one of claims 1 to 14, configured to determine the cell-free hemoglobin interference threshold by the above. **Claim 16** The cell-free hemoglobin interference threshold is either low or high, the predetermined categorization scheme is one-dimensional and includes at least three categories, and the cell-free hemoglobin interference threshold is Low when the measured category and the adjusted category are the same or adjacent within the predetermined categorization scheme. High when the measured category and the adjusted category are not separated by at least one category within the predetermined categorization scheme. The apparatus (100) according to claim 15. **Claim 17** The analyte concentration is Potassium ion, Sodium ion, Calcium ion, Chloride ion, Creatinine, and Lactic acid The concentration of an analyte selected from the group consisting of. The apparatus (100) according to any one of claims 1 to 16. **Claim 18** The analyte concentration is a plurality of analyte concentrations of the analyte, and for at least two of the analytes, The data processing device (106) is Determining the cell-free hemoglobin interference threshold based on The cell-free hemoglobin concentration, and The analyte concentration And configured to output a signal (108) indicating the cell-free hemoglobin interference threshold when at least the cell-free hemoglobin interference threshold is within a predetermined range. ​ The relationship between the acellular hemoglobin interference threshold and the analyte concentration is different for each analyte, such as being specific for at least two analytes, the apparatus (100) according to any one of claims 1 to 17.

19. further comprising a user interface (112) arranged to receive user input and the data processing device is configured to determine the acellular hemoglobin interference threshold based on the user input, the apparatus (100) according to any one of claims 1 to 18.

20. For at least one first analyte concentration, a first change in the acellular hemoglobin interference threshold changes as the acellular hemoglobin concentration increases at a first acellular hemoglobin concentration, For at least one second analyte concentration, a second change in the acellular hemoglobin interference threshold changes as the acellular hemoglobin concentration increases at a second acellular hemoglobin concentration, wherein the first change and the second change are each substantially the same as or the same as the second change, such as corresponding to exceeding an acellular hemoglobin threshold, the first analyte concentration is less than the second analyte concentration, the first acellular hemoglobin concentration is different from the second acellular hemoglobin concentration, such as being less than or greater than the second acellular hemoglobin concentration, the apparatus (100) according to any one of claims 1 to 19.

21. The apparatus, which is, for example, a blood gas analyzer, further comprises: Carbon dioxide, such as CO ２ , Oxygen, for example O ２ and pH arranged to further measure the concentration in one or more or all of the liquid samples, the apparatus (100) according to any one of claims 1 to 20.

22. A method (700) for automatically measuring the analyte concentration in a liquid sample (102) containing an analyte and acellular hemoglobin, and for automatically determining the acellular hemoglobin interference threshold, comprising: a. measuring the analyte concentration in the liquid sample (720); b. measuring the acellular hemoglobin concentration in the liquid sample (722); c. providing to a data processing device (106) comprising a processor the analyte concentration, the acellular hemoglobin concentration ; d. using the data processing device to the acellular hemoglobin concentration, and the analyte concentration a step (724) of automatically determining the cell-free hemoglobin interference threshold based thereon; e. a step (726) of outputting, from the data processing device, a signal indicating the cell-free hemoglobin interference threshold when at least the cell-free hemoglobin interference threshold is within a predetermined range A method (700) comprising: **Claim 23** The determination of the cell-free hemoglobin interference threshold is further based on a predetermined categorization scheme, for example, the predetermined categorization scheme enables categorizing a liquid sample based on an analyte concentration, The method determines the measured category of the liquid sample based on the analyte concentration, such as attributing the analyte concentration to a specific clinical picture measured, determining an adjusted concentration, such as an adjusted analyte concentration, where the adjusted concentration is adjusted with respect to the interference effect of the cell-free hemoglobin, based on the analyte concentration, such as the measured analyte concentration, the interference effect of the cell-free hemoglobin is based on the cell-free hemoglobin concentration, determining an adjusted concentration, determining the adjusted category of the liquid sample based on the adjusted concentration, such as attributing the adjusted analyte concentration to an adjusted specific clinical picture, and determining the cell-free hemoglobin interference threshold based on the degree of difference between the measured category and the adjusted category The method (700) according to claim 22, comprising the step of determining the cell-free hemoglobin interference threshold by: **Claim 24** The liquid sample (102) is at least partially, for example, partially or wholly, a sample containing cells such as red blood cells, a sample derived from a sample containing cells such as red blood cells, a whole blood sample such as a human whole blood sample, or a diluted whole blood sample and / or a sample derived from a whole blood sample such as serum or plasma, for example, a sample derived from a human whole blood sample, which is a fraction of a human whole blood sample. The method (600) according to claim 22 or 23. **Claim 25** A computer program, such as a computer program product, which when executed by a computer, receives first information based on an analyte concentration, receives second information based on a cell-free hemoglobin concentration, determines a cell-free hemoglobin interference threshold based on the cell-free hemoglobin concentration, and the analyte concentration and Outputting a signal indicating the acellular hemoglobin interference threshold when at least the acellular hemoglobin interference threshold is within a predetermined range (726). A computer program including instructions causing a computer to perform the above.

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