JP5771652B2 - System and method for determining the amount of blood in a blood culture - Google Patents

Description

  An improved system and method for determining the amount of blood in a blood culture in a container is disclosed.

Fast and reliable detection of microorganisms in the blood is one of the most important tasks of a clinical microbiology laboratory. Several different blood culture systems and methods are available in the laboratory. For example, BACTEC® radiometric and non-radiometric systems (Becton Dickenson Diagnostic Instrument Systems, Sparks, Maryland) are often used for this task. For example, the BACTEC® 9240 device houses up to 240 blood culture vessels and functions as an incubator, agitator, and detection system. Each vessel includes a fluorescent CO ₂ sensor that is continuously monitored (eg, every 10 minutes). Rather than using growth index thresholds or delta values, the culture is identified as positive by a computer algorithm for growth detection based on the rate of increase or sustained increase in changes in CO ₂ production. BACTEC® 9240 is fully automatic after the container is installed.

  The optimal performance of a blood culture system such as BACTEC® 9240 depends on the collection of the correct amount of blood per sample. Culturing less than the optimal level of the sample can affect the recovery of the organism based on the reduced likelihood of obtaining a living organism from a limited blood volume. Incubating more than the optimal level of the sample may result in failure to properly dilute or remove inhibitors in the sample, or undesirable competition in which blood competes with any microorganisms present in the sample for nutrients such as oxygen and sugar A situation can occur, thereby exceeding the design characteristics of the medium, which can reduce the recovery rate of living organisms. Blood can also affect the performance of the system by concealing the presence of growth if growth is present. For example, signal acceleration can be used to detect the presence of microorganisms that are assimilated into blood background signals when too much or too little blood is cultured.

  In view of the above, what is needed in the art is a method for determining the amount of blood in a culture. The ability to actually determine the amount of blood in the culture identifies, for example, feedback systems for blood culture quality (including phlebotomy feedback), containers that are extremely over or underfilled during the protocol. (Warning staff that the quality of the culture is low), allowing the ability to adjust the ingrowth detection algorithm based on the presence of different levels of blood.

US Pat. No. 6,432,697 US Pat. No. 6,617,127 US Pat. No. 6,096,272 US Pat. No. 4,889,992 International Publication No. 20066071800 Pamphlet US Pat. No. 6,900,030

Stanier et al., 1986, The Microbial World, 5th edition, Prentice-Hall, Englewood Cliffs, New Jersey, pages 10-20, 33-37, and 190-195 Oberoi et al. 2004, "Comparison of rapid colorimetric method with conventional method in the isolation of mycobacterium tuberculosis," Indian J Med Microbiol 22: 44-46

  To meet the needs found in the prior art, systems, methods, and apparatus are provided for determining the amount of blood (eg, blood volume) in a blood culture vessel. For example, a metabolic rate that can be normalized to the amount of blood present, allowing an estimate of the amount of blood in the blood culture, allowing an estimate of the initial metabolic activity rate in the blood culture vessel, And a data transformation method was devised that provides an estimate of the metabolic rate over time. This determination of the volume of blood can be used for quick feedback to the user if too much blood is added to the vial. This will prompt the user to split the sample for more accurate results. Thus, the systems and methods of the present invention can provide a number of useful applications in microbiology and related fields, with particular applications in cell culture sterilization test methods.

  In one aspect, the present invention provides a method for determining the amount of blood in a blood culture in a container. In this method, the initial biological state of the blood culture in the container is measured at an initial time point. A plurality of measurements of the biological state of the blood culture in the container is then performed, with each measurement in the plurality of measurements being performed at a different time between the first time point and the second time point. For each measurement in the plurality of measurements, a normalized relative value is calculated between the individual measurement and the initial biological state of the blood culture, thereby obtaining a plurality of normalized relative values. The plurality of normalized relative values can be divided into predetermined constant intervals at a plurality of time points between the first time point and the second time point, with respect to time. For example, the first predetermined constant interval can include a first ten normalized relative value, the second predetermined constant interval can include a next ten normalized relative value, This is repeated until time point 2 is reached. For each of these individual predetermined constant intervals of the plurality of time points between the first time point and the second time point, determining a first derivative of the normalized relative value at each predetermined predetermined interval; Thereby, a plurality of rate transformation values are obtained.

  In such an embodiment, there is a rate transformation value for each predetermined constant interval of time. The multiple rate transformation values can be considered to include multiple sets of rate transformation values. Each individual set of rate transformation values is for a different set of successive time points between the first time point and the second time point. For example, the first set of rate transformation values can be the first seven rate transformation values in a plurality of rate transformation values, and the second set of rate transformation values can be a plurality of rate transformation values. It can be the next seven rate transformation values in the value and this is repeated. For each individual set of rate transformation values in multiple sets of rate transformation values, calculate the average relative transformation value as a representative value for each rate transformation value in the individual set of rate transformation values . In this way, a plurality of average relative transformation values are calculated. In some embodiments, the representative value of the plurality of average relative transformation values is compared to an optional lookup table that matches the representative value of the plurality of average relative transformation values to the blood volume, thereby Determine the amount of blood in the blood culture.

  In some embodiments, the amount of blood in the blood culture in the container is output to a user interface device, monitor, computer readable storage medium, computer readable memory, or a local or remote computer system. In some embodiments, the amount of blood in the blood culture in the container is displayed. In some embodiments, the first time point is 1 hour or more after the initial time point and the second time point is 4 hours or more after the initial time point. In some embodiments, the first time point is 1.5 hours to 3 hours after the initial time point and the second time point is 4.5 hours to 5.5 hours after the initial time point. .

  In some embodiments, the representative value of the rate transformation value in the first set of rate transformation values in the plurality of sets of rate transformation values is a value for each rate transformer in the first set of rate transformation values. Includes geometric mean, arithmetic mean, median, or mode of formation values. In some embodiments, the representative value of the plurality of average relative transformation values includes a geometric mean, arithmetic average, median, or mode of the plurality of average relative transformation values.

  In some embodiments, the measurements in the plurality of measurements of the biological state of the blood culture are each measured from the blood culture at periodic time intervals between the first time point and the second time point. For example, in some embodiments, the periodic time interval is 1 minute to 20 minutes, 5 minutes to 15 minutes, 30 seconds to 10 minutes, every 10 minutes, 8 minutes to 12 minutes, and the like.

  In some embodiments, each average relative transformation value in the plurality of average relative transformation values that is lower than the first threshold or higher than the second threshold is a representative value of the plurality of average relative transformation values. Exclude from multiple average relative transformation values before calculating. In such an embodiment, each average relative transformation value excluded from the plurality of average relative transformation values affects a representative value of the plurality of average relative transformation values that are compared to an optional lookup table. Absent.

In some embodiments, the initial biological state of the blood culture is determined by the fluorescence output of a sensor in contact with the blood sample. For example, in some embodiments, the amount of sensor fluorescence output is affected by CO ₂ concentration, O ₂ concentration, or pH.

  In some embodiments, 10 to 50,000 measurements of the biological state of the blood culture in the container, 100 to 10,000 measurements, 150 to 5,000 measurements, 100 to 1000 measurements, 50 To 500 measurements, more than 10, more than 100 measurements (for example, between the first time point and the second time point). In some embodiments, each of the individual predetermined regular intervals of the plurality of time points includes a respective rate transformation value for the time point in the time window between the first time point and the second time point, or Consists of rate transformation values. In some embodiments, this time window is a period of 20 minutes to 5 hours, a period of 20 minutes to 2 hours, a period of 30 minutes to 90 minutes, a period of 20 minutes to 1 hour, or a period of more than 30 minutes.

  In some embodiments, each set of rate transformation values in a plurality of rate transformation values is from 4 to 20 consecutive rate transformation values, from 5 to 15 consecutive rate transformation values, or from 2 to 1000 It includes or consists of consecutive rate transformation values, or more than 5 consecutive rate transformation values. In some embodiments, there are 5 to 500, 20 to 100, or 10 to 10,000 average relative transformation values among the plurality of average relative transformation values. In some embodiments, the amount of blood in the blood culture is 1 ml to 150 ml, 2 ml to 100 ml, 0.5 ml to 80 ml, 0.5 ml to 10,000 ml, or 0.25 ml to 100,000 ml. In some embodiments, the blood culture is 1% to 99% of the culture volume, 5% to 80% of the culture volume, 10% to 75% of the culture volume, Less than 80% or more than 10% of the culture volume. In some embodiments, the blood culture is 1% to 99% of the total weight of the culture, 5% to 80% of the total weight of the culture, 10% to 75% of the total weight of the culture, Less than 80% of the total weight or more than 10% of the total weight of the culture.

  In some embodiments, the container comprises a sensor composition in fluid communication with the blood culture, and the sensor composition is irradiated with light comprising a wavelength that causes the fluorescent compound to fluoresce when exposed to oxygen. The fluorescent compound whose fluorescence characteristics change when applied. Furthermore, the presence of the sensor composition is non-destructive for blood cultures. In such an embodiment, the initial biological state measurement comprises irradiating the sensor composition with light comprising a wavelength that causes the fluorescent compound to fluoresce, and irradiating the sensor composition with light from the fluorescent compound. Observing the intensity of the fluorescent light. In some embodiments, the fluorescent compound is included in a substrate that is relatively impermeable to water and non-gaseous solutes but highly permeable to oxygen. In some embodiments, the substrate comprises rubber or plastic.

  In another aspect, the present invention provides a blood volume determination apparatus that includes a processor and a memory connected to the processor and that determines the volume of blood in the blood culture in the container. The memory is an optional lookup table comprising a match between (i) a first set of values for a representative value of a plurality of average relative transformation values and (ii) a set of blood volumes. For each value relative to a representative value of the plurality of average relative transformation values in the first set, a lookup table may be provided in which a corresponding blood volume exists in the blood volume set. In some embodiments, the memory is an electronically encoded instruction that causes a processor (e.g., a microprocessor) to automatically measure the initial biological state of the blood culture in the container at an initial time point, And a blood volume determination module including electronically encoded instructions that cause the processor to make multiple measurements of the biological state of the blood culture in the container. Each measurement in the plurality of measurements is of a different time point between the first time point and the second time point. The blood volume determination module calculates a normalized relative value between each measurement and the initial biological state of the blood culture for each measurement of multiple measurements, thereby Instructions for obtaining relative values can be further included.

  The blood volume determination module is configured to obtain a normalized relative value at each predetermined fixed interval of the plurality of time points for each of the predetermined predetermined intervals of the plurality of time points between the first time point and the second time point. Further comprising electronically encoded instructions that cause the processor to determine the first derivative of, thereby obtaining a plurality of rate transformation values. The multiple rate transformation values include multiple sets of rate transformation values, and each set of rate transformation values in the multiple sets of rate transformation values is between the first time point and the second time point. Are different sets of successive points in time. The blood volume determination module determines an average relative transformation value as a representative value for each rate transformation value in an individual set of rate transformation values for each set of rate transformation values in multiple sets of rate transformation values. May further include electronically encoded instructions that cause the processor to calculate and thereby calculate a plurality of average relative transformation values. The blood volume determination module causes the processor to compare the representative value of the plurality of average relative transformation values with an optional lookup table that matches the representative value of the plurality of average relative transformation values to the blood volume, thereby Electronically encoded instructions may be further included to determine the amount of blood in the blood culture in the container.

  In another aspect, the present invention provides a computer readable medium storing a computer program product that is executable by a computer to determine the amount of blood in a blood culture in a container. The computer program product is a lookup table that includes a match between (i) a first set of values for a representative value of a plurality of average relative transformation values and (ii) a set of blood volumes, For each value relative to a representative value of the plurality of average relative transformation values in the first set, a lookup table may be included in which a corresponding blood volume exists in the blood volume set. The computer program product can further include a blood volume determination module as described above together with a blood volume determination device.

  In another aspect, the present invention provides a blood volume determination apparatus comprising a processor for performing any of the methods disclosed herein and a memory connected to the processor. In yet another aspect, the present invention provides a computer readable medium storing a computer program product that is executed by a computer to determine the amount of blood in a blood culture in a container. The computer program product includes instructions for performing any of the methods disclosed herein.

  In another aspect, the present invention provides a method for determining the amount of blood in a blood culture in a container. In this method, multiple measurements are obtained. Each measurement in the plurality of measurements is performed at a different time point between the first time point and the second time point. Then, for each of the individual predetermined intervals of the plurality of time points between the first time point and the second time point, the measurement of the biological state at each of the predetermined time intervals of the plurality of time points. A first derivative is determined, thereby obtaining a plurality of rate transformation values. The multiple rate transformation values include multiple sets of rate transformation values, and each set of rate transformation values in the multiple sets of rate transformation values is between the first time point and the second time point. For different sets of successive time points. For each individual set of rate transformation values in multiple sets of rate transformation values, the average relative transformation value is calculated as a representative value for each rate transformation value in the individual set of rate transformation values. This calculates a plurality of average relative transformation values. The amount of blood in the blood culture in the container is then determined based on a representative value of a plurality of average relative transformation values. In some embodiments, the determining step compares the representative value of the plurality of average relative transformation values with an optional lookup table that matches the representative value of the plurality of average relative transformation values to the amount of blood. And thereby determining the amount of blood in the blood culture in the container. In other embodiments, this determining step can be performed by an equation that gives the volume of blood as a function of a representative value of a plurality of average relative transformation values.

FIG. 2 illustrates a blood volume determination device for determining the volume of blood in a blood culture in a container, comprising a processor and a memory connected to the processor, according to an embodiment of the present invention. 1 is a schematic diagram of a blood culture container and CO ₂ detection system according to an embodiment of the present invention. FIG. 3 illustrates a method for determining the amount of blood in a blood culture in a container according to an embodiment of the present invention. FIG. 3 illustrates a method for determining the amount of blood in a blood culture in a container according to an embodiment of the present invention. FIG. 4 is a plot of normalized relative values measured from blood cultures in a container according to an embodiment of the invention. FIG. 5 is a plot of average relative transformation values over time based on the average rate of change of the rate transformation values of FIG. 4 over time, in accordance with an embodiment of the invention. FIG. 5 is a plot of the second derivative of the normalized relative value of FIG. 4, showing the change in metabolic rate over time according to an embodiment of the present invention. In accordance with an embodiment of the present invention, the ART blood mean (herein, selected mean relative), along with a regression line demonstrating a 98.1% correlation between ART blood mean and blood volume. It is a figure which illustrates the plot with respect to the value of the volume of blood corresponding to the representative value of a transformation value). According to the embodiment of the present invention, the ART blood median to the corresponding blood volume value, with a regression line demonstrating a 98.1% correlation between ART blood median and blood volume. It is a figure which illustrates a plot.

  In the several scenes of each drawing, like reference numerals refer to corresponding parts.

  Systems, methods, and apparatus are provided for determining the amount of blood in a blood culture that obtains an initial biological state of the culture and then makes periodic measurements of the biological state. For each measurement, a normalized relative value is calculated between the individual measurement and the initial measurement, thereby obtaining a normalized relative value. For each interval at a plurality of time points represented by the normalized relative value, a first derivative of the normalized relative value at the interval is calculated, thereby obtaining a plurality of rate transformation values. For each set of rate transformation values in a plurality of rate transformation values, an average relative transformation value is calculated, thereby obtaining a plurality of average relative transformation values. A look-up table that matches the representative value of the average relative transformation value to the amount of blood can be used to determine the amount of blood in the blood culture.

5.1 Definitions As used herein, the term “biological state” includes, for example, CO ₂ concentration, O ₂ concentration, pH, rate of change of CO ₂ concentration, rate of change of O ₂ concentration, Or it refers to a measurement of the metabolic activity of a blood culture determined by the rate of change of pH.

  As used herein, the term “blood” refers to whole blood or one from the group of cell types composed of red blood cells, platelets, neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Means two, three, four, five, six or seven cell types. The blood can be from any species including, but not limited to, humans, any laboratory animal (eg, rat, mouse, dog, chimpanzee), or any mammal.

  The term “blood culture” as used herein refers to any amount of blood mixed with a blood medium. Examples of media include, but are not limited to, soy casein-added broth, soy casein digest, hemin, menadione, sodium bicarbonate, sodium polyanitol sulfonate, sucrose, pyridoxal HCK1, yeast extract, And L-cysteine. One or more reagents that can be used as a blood medium are described in, for example, Non-Patent Document 1, which is incorporated herein by reference in its entirety for such purposes. In some cases, a blood culture is obtained when a subject has symptoms of blood infection or bacteremia. Blood is drawn from the subject and placed directly into a container containing nutrient broth. In some embodiments, each container requires 10 ml of blood.

  The term “instance” as used herein refers to the execution of a step in an algorithm. Some steps in the algorithm are executed multiple times and each iteration of the step is called an instance of a step.

  As used herein, the term “microorganism” refers to organisms with a diameter of 1 mm or less excluding viruses.

  As used herein, the term “part” refers to at least 1%, at least 2%, at least 10%, at least 20%, at least 30%, at least 50%, at least 75%, at least 90%, or at least 99 of the set. %. Thus, in a non-limiting example, at least a portion of the plurality of subjects is at least 1%, at least 2%, at least 10%, at least 20%, at least 30%, at least 50%, at least 75% of the plurality of subjects. , At least 90%, or at least 99%.

  The term “subject” as used herein is an animal, preferably a mammal, more preferably a non-human primate, most preferably a human. The terms “subject”, “individual”, and “patient” are used interchangeably herein.

The term “container” as used herein refers to any container that can hold a culture, such as a blood culture. For example, in one embodiment, the container is a container having a side wall, a bottom wall, and an open upper end for receiving the culture to enter, which container can be used to visualize glass and turbidity in a sample. The container is preferably resistant to heating at a temperature of at least 250 ° C., and is formed from a material such as a transparent plastic (eg, a cyclic olefin copolymer) that has sufficient transparency to be observed. In some embodiments, the container has a wall thickness sufficient to withstand an internal pressure of at least 25 psi, and a lid attached to the open end of the container, and the culture is stored in the container. And substantially uncontaminated over long periods of time under ambient conditions. An exemplary container is described in U.S. Patent No. 6,057,028, which is incorporated herein by reference. In some embodiments, the long term under ambient conditions is at about 40 ° C. for at least about 1 year. In some embodiments, the container further comprises a fluorescent sensor compound immobilized on the inner surface of the container that, when exposed to oxygen, exhibits a decrease in fluorescence intensity when exposed to fluorescent light. In some embodiments, the container is substantially transparent to the fluorescent light. In some embodiments, the fluorescent sensor compound is tris-4,7-diphenyl-1,10-phenanthroline ruthenium (II) salt, tris-2,2′-bipyridyl ruthenium (II) salt, 9,10-diphenyl. At least one compound selected from the group consisting of anthracene and mixtures thereof. In some embodiments, the container is a Blood Culture BACTEC® LYTIC / 10 Anaerobic / F culture vial, a BBL® SEPTI-CHEK® vial, a BBL® SEPTI-CHEK® Trademark) blood culture bottle, Becton Dickinson BACTEC® vial, Plus Aerobic / F ^* and Plus Anaerobic / F ^* culture vial, Becton Dickinson BACTEC® Standard / 10 Aerobic / F culture vial, Becton D TM Myco / F Lytic culture vial, Becton Dickinson BACTEC® PEDS P US (registered trademark) / F culture vial or Becton Dickinson BACTEC (registered trademark) Standard Anaerobic / F culture vials (Becton Dickinson, Franklin Lakes, New Jersey), it is.

5.2 Exemplary Apparatus FIG. 1 shows an exemplary blood volume determination apparatus 11 for determining the volume of blood in a blood culture in a container, comprising a processor and a memory connected to the processor. Yes. The processor and memory illustrated in FIG. 1 can be part of, for example, an automated or semi-automated radiometric or non-radiometric blood culture system. The device 11 is
A central processing unit 22;
An optional non-volatile main memory 14 such as a hard disk drive, for example, which is controlled by the storage controller 12 and stores software and data;
A system memory 36, preferably high-speed random access memory (RAM), that stores system control programs, data, and application programs, and programs and data (optionally loaded from non-volatile storage 14) A system memory 36, which may include a read only storage element (ROM);
A user interface 32 including one or more input devices (eg, keyboard 28, mouse) and a display 26 or other output device;
A sensor 34 for measuring the biological state of the culture in the container;
A network interface card 20 (communication circuit) connected to the sensor 34;
An internal bus 30 interconnecting the above elements of the system;
A power supply 24 that supplies power to the above elements
Can be provided.

The operation of the central processing unit 22 is mainly controlled by the operating system 40.
The operating system 40 can be stored in the system memory 36. In a typical implementation, the system memory 36 is:
A file system 42 that controls access to the various files and data structures used by the present invention;
A blood volume determination module 44 that determines the volume (eg volume) of blood in the blood culture;
A biological state data structure 46 that stores a plurality of measurements of an initial biological state 48 of the blood culture and a biological state of the blood culture, wherein each measurement 50 in the plurality of measurements includes a first A biological data structure 46 performed at different times between the (initial) time point and the second (final) time point;
An optional lookup table 54 comprising a match between (i) a first set of values for a representative value of a plurality of mean relative transformation values and (ii) a set of blood volumes, A lookup table 54, for each value relative to a representative value of a plurality of average relative transformation values in the first set, a corresponding blood volume is present in the blood volume set;
A set of rate transformation values 60, each set of rate transformation values including a plurality of rate transformation values 62, each rate transformation value 62 being a normalized relative to a predetermined constant interval of time A set of rate transformation values 60, which is the first derivative of the values;
An average relative transformation value 66 for each set 60 of rate transformation values 60; and a data structure 68 that stores values indicative of the amount of blood in the culture in the container.
Is also included.

  As illustrated in FIG. 1, device 11 includes a biological state data structure 46, an optional lookup table 54, a set of rate transformation values 60, an average relative transformation value 66, and a blood culture in the container. Data such as the amount of blood 68 in the object can be included. In some embodiments, the memory 36 or data store 14 also stores representative values of the average relative transformation value 66. The above data may be in any form of data storage, including but not limited to flat files, relational databases (SQL), or online analytical processing (OLAP) databases (MDX and / or variants thereof). it can. In some embodiments, such data structures are not stored as cubes, but are stored in a database that includes a star scheme with dimension tables that define hierarchies. Further, in some embodiments, such data structures are stored in a database having a hierarchy that is not clearly classified in the underlying database or database scheme (eg, dimension tables that are not hierarchically arranged). In some embodiments, such a data structure is stored in device 11. In other embodiments, all or part of these data structures are stored (stored) in one or more computers addressable by the device 11 over the Internet / network not shown in FIG. In some embodiments, all or some of the one or more program modules shown in the apparatus 11 of FIG. 1, such as the blood volume determination module 44, are actually internet / not shown in FIG. It exists in a device (for example, a computer) other than the device 11 that can be addressed by the device 11 via a network.

The apparatus 11 determines the metabolic activity value of the blood culture based on, for example, the CO ₂ concentration, O ₂ concentration, pH, CO ₂ concentration change rate, O ₂ concentration change rate, or pH change rate in the blood culture. To do. By determining this metabolic activity, the device 11 can determine the amount of blood in the blood culture. In some embodiments, the device 11 contains a number of blood culture vessels and serves as an incubator, stirrer, and detection system. These elements of the device 11 are not shown in FIG. 1 because the nature of such components varies greatly depending on the actual configuration of the device 11. For example, the number of culture containers accommodated by the device can range from one container to more than 1000 containers. There may be a sensor attached to each container to measure the biological state of the blood culture contained in the container. The sensors can be placed anywhere on the container and there are a wide range of possible sensors that can be used.

FIG. 2 illustrates one exemplary sensor that can measure the biological state of a blood culture. In FIG. 2, a CO ₂ sensor 204 is coupled to the bottom of the blood culture vessel 202 on which a certain amount of blood culture containing a mixture of blood and medium has been introduced. The CO ₂ sensor 204 is impermeable to ions, medium components, and blood, but is permeable to CO ₂ without restriction. The carbon dioxide produced by the blood diffuses into the sensor 204 and dissolves in the water present in the sensor substrate, producing hydrogen ions. As the hydrogen ion concentration increases (pH decreases), the fluorescence output of the sensor 204 increases, thereby changing the signal sent from the excitation filter 206 to the emission filter 208. The device 11 repeatedly measures the signal passing through the emission filter 208 over time and uses this data to determine the amount of blood in the blood culture using the algorithm disclosed herein.

  In some embodiments, the device 11 is an incubator, shaker, and fluorescence detector that holds from 1 to 1,000 culture vessels (eg, 96, 240, or 384 culture vessels). It is. In some embodiments, the containers are arranged in a rack (eg, a circular or linear rack), and each container has multiple container stations. For example, in one particular embodiment, apparatus 11 holds 240 containers arranged in 6 racks, each rack having 40 container stations. In some embodiments, each vessel station of apparatus 11 includes a light emitting diode and a photodiode detector with appropriate excitation and emission filters (eg, as illustrated in FIG. 2). In some embodiments, the container is shaken and heated at 35 ± 1 ° C.

5.3 Exemplary Method Now that an exemplary apparatus according to the present invention has been described, an exemplary method according to the present invention will be described in detail. In some embodiments, such a method can be implemented by the blood volume determination module 44 of FIG. Without being bound by a particular method or theory, the principle of blood volume determination is based on the measurement of the initial relative metabolic rate of blood in the sample when it is placed in the system. Blood is a suspension of living eukaryotic cells that, when placed in the medium, continues to metabolize for 48 hours after entering the system. The initial metabolic rate, and possibly the initial metabolic rate, can also provide information about the amount of blood cells present in the blood culture (and thus the amount of blood). Referring to step 302 of FIG. 3, the initial biological state of the culture is obtained. For example, referring to FIG. 2, in some embodiments, the initial value of detector 204 is read to determine the CO ₂ concentration of the sensor. In an alternative embodiment, the initial O ₂ concentration, pH, or other indicator of the biological state of the culture is read (measured) at step 302. In some embodiments, the initial biological state of the blood culture is determined by the fluorescence output of a sensor (eg, sensor 204) that is in contact with the blood culture. In some embodiments, the amount of fluorescence output of the sensor is affected by the CO ₂ concentration as described above in conjunction with FIG. In some embodiments, the amount of sensor fluorescence output is affected by O ₂ concentration, pH, or other indicators of metabolic status known in the art. In general, any observable parameter (eg, O ₂ concentration, CO ₂ , concentration, etc.) indicative of the metabolic rate of the culture can be measured and stored as the initial state. In some embodiments, this physically observable is the accumulation of molecular products (eg, lipopolypolysaccharide with gram-negative bacteria), non-molecular physical / chemical changes (pressure) related to growth. Change), and / or the production of accumulated carbon dioxide or other metabolites or the consumption of substances such as oxygen) or the accumulation of cellular material.

In some embodiments, the initial biological state of the blood culture is obtained at step 302 using a colorimetric, fluorescent, turbidimetric, or infrared method. Examples of colorimetric methods include, but are not limited to, resazurin / colorimetric redox indices such as methylene blue and tetrazolium chloride, or described in US Pat. Use of p-iodonitrotetrazolium violet compounds that are included. Another example of a colorimetric method includes the colorimetric assay used in Non-Patent Document 2, which is incorporated herein by reference in its entirety. In Oberoi et al. (Non-Patent Document 2), an MB / Bact240 system (Organon Teknika) is equipped with a culture vessel. The operating principle of this system is based on the detection of mycobacterial growth by a colorimetric sensor. In the presence of the organism, CO ₂ is produced when the organism metabolizes the substrate glycerol. The color of the gas permeability sensor at the bottom of each culture vessel increases the reflectivity of the device monitored by the system using infrared light. Examples of colorimetric method, further includes any monitoring color change of the sensor composition due to changes of the gas components such as CO ₂ concentration in the container resulting from the metabolism of microorganisms.

  Examples of fluorometric and colorimetric methods are incorporated herein by reference in their entirety, there are multiple light sources that each emit light of a different wavelength for colorimetric and fluorescent detection, and incubation Patent Document 3 discloses an equipment system including a rotating rack for an index. As used herein, turbidimetric analysis refers to measuring the turbidity of a culture using a nephelometer. A nephelometer is an instrument that measures suspended particles in a liquid or gaseous colloid. This measurement is performed by using a light beam (light source beam) and a photodetector set on one side of the light source beam (usually 90 degrees). Thus, the particle density is a function of the light reflected from the particles into the detector. To some extent, how much light is reflected by a given density of particles depends on the properties of the particles, such as the shape, color, and reflectivity of the particles. Therefore, the establishment of a behavioral correlation between turbidity and suspended solids (more useful but typically more difficult particulate quantification) must be done individually for each situation .

  Infrared methods for measuring the biological state of blood cultures as used herein are not limited, but are described in US Pat. Any infrared microbial detection system or method known in the art, including those disclosed.

  In some embodiments, the container 202 holding the blood culture includes a sensor composition 204 in fluid communication with the blood culture. The sensor composition 204 includes a fluorescent compound that, when exposed to oxygen, changes its fluorescence characteristics when irradiated with light that includes a wavelength that causes the fluorescent compound to fluoresce. The presence of the sensor composition 204 is non-destructive for the blood culture. In such an embodiment, measuring step 302 (and each instance of measuring step 308) includes irradiating sensor composition 202 with light that includes a wavelength that causes the fluorescent compound to fluoresce, and irradiating the sensor composition with this light. While observing the intensity of the fluorescent light from the fluorescent compound. In some embodiments, the fluorescent compound is included in a substrate that is relatively impermeable to water and non-gaseous solutes but highly permeable to oxygen. In some embodiments, the substrate comprises rubber or plastic. Further details of the sensor according to this embodiment of the invention are disclosed in US Pat.

  At step 304, the initial biological state of the blood culture measured at the start of step 302 is normalized and stored as the initial biological state 48 of the blood culture (eg, 100 percent or other predetermined value). Against). This initial biological fluid state, stored as data element 48 of FIG. 1, serves as a reference value for subsequent measurements of the biological state of the blood culture. In some embodiments, step 304 is not performed and the absolute measurement of step 302 is used in the algorithms disclosed herein.

  The device 11 incubates the blood culture for a predetermined time after the initial biological state measurement is performed. Then, after a predetermined time has elapsed, the device 11 makes another measurement of the biological state of the blood culture. This process is illustrated by steps 306 and 308 in FIG. In FIG. 3A, this process is illustrated as proceeding to time step t of step 306. The biological state during step 306, waiting for the device to progress by time step t, is not used in subsequent processing steps that identify the blood volume in the blood culture. In step 308, as time progresses by time step t, the measurement of the biological state of the blood culture in the container is performed again in the same manner as the initial measurement of the biological state was made (eg, Using the apparatus shown in FIG. In some embodiments, the predetermined period (the length of time step t) is 10 minutes. In some embodiments, the predetermined period (the length of time step t) is less than 5 minutes, less than 10 minutes, less than 15 minutes, less than 20 minutes, 1 to 30 minutes, Or it is a period exceeding 5 minutes. In some embodiments, measuring the biological state of the blood culture is performed at step 308 by a colorimetric, fluorescent, turbidimetric, or infrared method. Normalize the measurement of step 308 to the initial measurement of step 302 in an embodiment where the measurement of the biological state of the blood culture in the container made in step 308 is used to normalize the initial measurement of step 302 To convert to a normalized relative value. In one embodiment, the biological state measurement of the blood culture in the container made in step 308 is converted to a normalized relative value by taking the ratio of the measurement in step 308 to the initial measurement in step 302. . In some embodiments, this calculated normalized relative value is stored as data element 50 of FIG. In some embodiments, the biological state measurement measured in step 308 is stored as data element 50 of FIG. 1, and the normalized relative value corresponding to the biological state measurement measured in step 308 is: Calculate in subsequent processing steps as needed.

  At step 310, a determination is made as to whether a first predetermined time interval has elapsed. For example, in some embodiments, the predetermined constant time interval is 70 minutes. In this example, if the time step t of step 306 is 10 minutes, the time step t needs to advance seven times before state 310-Yes is achieved. In some embodiments, the predetermined fixed time interval is a time interval of 5 minutes to 5 hours, a time interval of 30 minutes to 10 hours, a time interval of less than 24 hours, or a time interval of more than 24 hours. When the first predetermined time interval has elapsed (310-Yes), process control proceeds to step 312 where an additional step of the algorithm is performed. If the first predetermined period of time has not elapsed (310-No), the process is instructed by the time t before the process control again measures the biological state of the blood culture in a new instance of step 308. Return to step 306 to wait for time to advance.

  The final result of steps 306-310 is a plurality of measurements of the biological state of the blood culture in the container, each measurement of which is a first (initial) time point and an end (final) time point. And at different points in time. Further, in an exemplary embodiment where the time step t is the same amount in each instance of step 306, each of the measurements in the multiple measurements of the blood culture is made at periodic intervals. In some embodiments, the periodic interval is an amount of time between 1 and 20 minutes, an amount of time between 5 and 15 minutes, an amount of time between 30 seconds and 5 hours, Or an amount of time exceeding 1 minute.

  When the predetermined fixed intervals have passed (310-Yes), the first derivative of the normalized relative value at each predetermined fixed interval (or, in an embodiment where normalization has not been performed, the step at each predetermined fixed interval). (Absolute value from 302) is calculated in step 312 to obtain the rate transformation value 62. In other words, the change in normalized relative value during a predetermined fixed interval is determined at step 312. In embodiments that normalize the measurement data, the rate transformation value is the first derivative of the normalized relative value, and in embodiments that do not normalize the measurement data, the rate transformation value is the first order of the absolute measurement in step 302. Note that it is a derivative. In some embodiments, the predetermined constant time interval for calculating the first derivative is all measurements in the immediately preceding time interval that is between 20 minutes and 2 hours. For example, in some embodiments, the predetermined constant time interval of step 310 is 70 minutes, and in step 312, the change over all normalized relative values of the measurements in this 70 minute interval (past 70 minutes). The rate is determined at step 312 and stored as a rate transformation value 62. In some embodiments, the predetermined fixed time interval (time window) for calculating the first derivative is 5 minutes to 2 hours, 30 minutes to 10 hours, 20 minutes to 2 hours, 20 minutes to 10 hours, or 30 minutes to 90 minutes. All measurements in the immediately preceding time interval between.

At step 314, a determination is made as to whether a predetermined number of rate transformation values have been measured since the last time condition 314-Yes. If so (314-Yes), process control proceeds to step 316. If not measured (314-No), process control returns to step 306, where process control waits until time step t has elapsed, and then continues to step 308 where the normalized relative value of the blood culture is again determined. calculate. Each condition (314-Yes) indicates the completion of the set 60 of rate transformation values 62. For example, in some embodiments, condition 314-Yes is achieved when seven new rate transformation values 62 are measured. In this example, the set of rate transformation values 60 includes or consists of seven rate transformation values. In some embodiments, each set 60 of rate transformation values 62 includes or consists of 4 to 20 consecutive rate transformation values 62. The continuous rate transformation value 62 is the rate transformation value in the same set 60.
Such a rate transformation value 62 is calculated and stored, for example, in successive instances of step 312. In some embodiments, each set 60 of rate transformation values 62 in a plurality of rate transformation values is 5 to 15 consecutive rate transformation values 62 and 1 to 100 consecutive rate transformations. It includes or consists of the value 62, more than 5 rate transformation values 62, or less than 10 rate transformation values 62.

  If condition 314-Yes is achieved, step 316 is performed. In step 316, an average relative transformation (average rate of change) value 66 is calculated from the newly formed set of rate transformation values 62. Thus, there is an average relative transformation value 66 for each set 60 of rate transformation values 62. In some embodiments, the average relative transformation (average rate of change) value 66 is newly formed by taking a representative value of the rate transformation value 62 in the set 60 of the newly formed rate transformation value 62. Calculate from a set 60 of rate transformation values 62. In some embodiments, this representative value is the geometric mean, arithmetic mean, median, or mode of all or some of the rate transformation values 62 in the newly formed set of rate transformation values 62. is there.

At step 318, a determination is made as to whether a predetermined point in the protocol has been reached. This predetermined point is the final time point, also known as the end point or the second time point. In some embodiments, the second time point is reached 1 hour or more, 2 hours or more, 10 hours or more, 3 hours to 100 hours, less than 20 hours after the initial measurement in step 302 (318). -Yes).
In some embodiments, the second time point is, in the instance of step 308, 10 to 50,000, 100 to 10,000 measurements of the biological state of the blood culture in the container, or It is reached when it is performed 150 to 5,000 times, more than 10, more than 50 times, more than 100 times (318-Yes). If the predetermined point of the protocol has not been reached (318-No), process control returns to step 306 where process control waits for time step t to proceed before starting another instance of step 308 where blood The biological state of the culture is again measured and used to calculate normalized relative values. If the predetermined point of the protocol has been reached (318-Yes), process control proceeds to step 320.

  At step 320, all average relative transformation (average rate of change) values 66 between a first predetermined time point and a second predetermined time point in the protocol are determined. In some embodiments, all average relative transformation values 66 calculated in successive instances of step 316 are considered to be between the first predetermined time point and the second predetermined time point. In such an embodiment, step 302 is not necessary. In some embodiments, the first time point is one hour or more after the initial time point in step 302 and the second time point is the initial time point if the initial biological state measurement was made. 4 hours later. In some embodiments, the first time point is 1.5 hours to 3 hours after the initial time point and the second time point is 4.5 hours to 5.5 hours after the initial time point. . In some embodiments, the first time point is 0.5 hours to 10 hours after the initial time point, and the second time point is 5 hours to 30 hours after the first time point.

  In an optional step 322, the average relative transformation value 66 that is lower than the first threshold or higher than the second threshold is eliminated. In some embodiments, the first threshold is a value between 0.01 and 5 (eg, 0.5). In some embodiments, the second threshold is a value between 50 and 500 (eg, 100). Each average relative transformation value excluded from the plurality of average relative transformation values at step 322 does not affect the representative value of the plurality of average relative transformation values 66 calculated at step 324.

  In step 324, representative values of all average relative transformation values 66 (except all that were excluded in optional step 322) are calculated. In some embodiments, the representative value is the geometric mean, arithmetic mean, median, or mode of the plurality of mean relative transformation values 66. In some embodiments, the plurality of average relative transformation values have an average relative transformation value 66 of 5 to 500, 20 to 100, greater than 100, or less than 10,000.

  In some embodiments of step 326, the representative value of the plurality of average relative transformation values 66 calculated in step 324 is used to find a match in the optional lookup table 54. As illustrated in FIG. 1, the lookup table 54 includes a plurality of representative values 56 and a plurality of blood volumes 58. For each representative value 56 in the plurality of representative values 56, there is a corresponding blood volume 58 among the plurality of blood volumes. In step 326, the representative value 56 that best matches the representative value calculated in step 324 is determined. The amount of blood 58 corresponding to this certified representative value 56 is then considered to be the amount of blood 68 in the blood culture in the container. Lookup table 54 is created at a time prior to step 326 using the calibrated amount of blood in the blood culture. In some embodiments, the amount of blood 68 in the blood culture is expressed in units of volume. For example, in some embodiments, the amount of blood 68 in the blood culture is 1 to 40 ml, 2 to 10 ml, or 1 to 1000 L. In some embodiments, the amount of blood 68 in the blood culture is expressed by weight, mass, concentration, or other metric. In some embodiments, rather than using an optional look-up table, the volume of blood is determined using one or more adjusted classifiers or other forms of waited equations.

  In some embodiments, the method uses a user interface device (eg, 32), a monitor (eg, 26), a computer readable storage medium (eg, 14 or 36) to determine the amount of blood 68 in the blood culture in the container. ), A computer readable memory (eg, 14 or 36), or a local or remote computer system. In some embodiments, the amount of blood in the culture in the container is displayed. As used herein, the term local computer system means a computer system directly connected to the device 11. As used herein, the term remote computer system means a computer system connected to the device 11 via a network such as the Internet.

5.4 Exemplary Computer Program Product and Computer The present invention can be implemented as a computer program product that includes a computer program mechanism embedded in a computer readable storage medium. Furthermore, any method of the present invention may be implemented on one or more computers. Moreover, any method of the present invention can be implemented in one or more computer program products. Some embodiments of the present invention provide a computer program product that encodes any or all of the methods disclosed herein. Such methods can be stored on a CD-ROM, DVD, magnetic disk storage product, or any other computer readable data or program storage product. Such a method can also be incorporated into a permanent storage device such as a ROM, one or more programmable chips, or one or more application specific integrated circuits (ASICs). Such permanent storage can be localized to a server, 802.11 access point, 802.11 wireless bridge / station, repeater, router, mobile phone, or other electronic device. Such a method encoded in a computer program product can also be distributed electronically by transmission of computer data signals over the Internet or other methods.

  Some embodiments of the present invention provide a computer program product that includes any or all of the program modules and data structures shown in FIG. These program modules can be stored on a CD-ROM, DVD, magnetic disk storage product, or any other computer readable data or program storage product. Program modules can also be incorporated into permanent storage devices such as ROM, one or more programmable chips, or one or more application specific integrated circuits (ASICs). Such permanent storage can be localized to a server, 802.11 access point, 802.11 wireless bridge / station, repeater, router, mobile phone, or other electronic device. The software modules of the computer program product can also be distributed electronically by transmission of computer data signals over the Internet or other methods.

5.5 Kits Some embodiments of the invention can also include kits for performing any of the methods disclosed herein. By way of non-limiting example, containers, blood cultures, and additional agents and software for performing any combination of the methods disclosed herein can be included in the kit. Thus, the kit contains one or more of these reagents in a suitable container means.

Software, containers, and kit components other than radiometric or non-radioactive systems can be packaged in aqueous media or in lyophilized form. Suitable container means of the kit generally include at least one vial, test tube, flask, bottle, syringe, or other container means that can contain the components and preferably be appropriately aliquoted. If more than one component is present in the kit, the kit will generally also include a second, third, or other additional container in which additional components can be placed separately. However, various combinations of components can be included in the vial. The kits of the present invention also typically include a means for containing the reagent container in tight containment for sale.
Such containers can include injection molded or blow molded plastic containers in which the desired vials are held.

6 Example A method was developed for the determination of the volume of a biological sample in a culture vessel. This method described herein illustrates the use of this method in a BACTEC® blood culture system (Becton Dicken Diagnostics Instrument Systems, Sparks, Maryland) to determine the volume of blood in a blood culture. To do. The BACTEC® blood culture system uses a fluorescent sensor to monitor changes in metabolic activity within the reagent with a series of corrected fluorescent signal data collected at 10 minute intervals from sensors placed in the culture reagent. The data used in this example was collected from the BACTEC® device used in the internal inoculum culture study or was collected during the clinical evaluation of this system. Data was stored and stored in a database containing container identification (by serial number and accession number), record of inoculation date, and amount of blood in the sample. Subsequently, the data transformation of the present invention was applied for analysis.

  Data transformation starts with an initial normalization of the vessel signal to a specific output (the initial state when it enters the system), called the initial biological state 48 of the blood culture, and all subsequent data (following) Biological status in the time interval was expressed as a percentage of its initial signal (normalized to 100 percent in these analyses). As data was collected with this system, data points were accumulated as a percentage of this initial signal. Each of these data points, expressed as a percentage of the initial signal, was a normalized relative value (NR) value.

  The calculated next value was the first derivative of the NR value because it changes over time. This value is the change rate (RT) value 62. The reference RT value used for these analyzes uses a period limit of 70 minutes. Any RT value 62 represents the percent change rate of the fluorescent signal over 70 minutes prior to its calculation.

  The next value calculated was the average rate transformation (ART) value. The ART value 66 is calculated as an average of the previous seven RT values 50 that have already been calculated, and serves as a smoothing function for the RT value 50.

  Examples of parameters calculated to determine blood volume are shown in FIGS. 4, 5, and 6. FIG. Escherichia coli cultures were analyzed using quantitative criteria (normalized relative value 50, rate transformation value 62, and average relative transformation value 66). The culture contained 3 ml of human blood from the subject and was inoculated with a suspension of E. coli (55 CFU) and placed in a BACTEC® 9000 device. The identifier 4942 is a unique identifier for the culture reported in FIGS. 4, 5, and 6 and can be used to link this culture data to the R & D BACTEC® database. . FIG. 4 shows a plot of normalized relative values over time. The vessel was placed in the apparatus and the temperature effect related to vessel equilibration was generally observed for the first hour. During the first hour, the signal stabilized and the background increased from 94 percent to 95 percent of the initial signal (this rate was due to blood activity). In a normalized relative plot (FIG. 4), growth was first visible after 8 hours and continued until 15 hours, with the final NR value approaching 126. A plot of the average relative transformation value 66 over time based on the average rate of change of the rate transformation value 62 of FIG. 4 over time is shown in FIG. Each average relative transformation (ART) value 66 is a measure of the average rate of change, and the maximum ART for this culture reached 1158 after 12.8 hours in culture. This shows the average maximum reached sensor change rate for this culture over a period of 1 hour. FIG. 6 is a plot of the second derivative of the normalized relative value 50, showing the rate change over time. This is due to the following critical points: the first acceleration point 602 (movement from 0), the maximum acceleration point 604 (maximum) where acceleration reaches its maximum (crossing zero point), the maximum point of deceleration (minimum) 606, And a graphical illustration showing the growth curve end point 608 (rate change returns to 0).

  By applying the transformation specified above in the blood culture system 11, it is possible to quickly determine what is happening metabolically in the container after the first 2 to 5 hours after the container is placed in the system 11. It becomes possible. Advantageously, as illustrated in FIGS. 7 and 8, the representative value of the average relative transformation value can be correlated to the volume of blood in the test sample. The data shown was generated from an extensive data set obtained from an external assessment of Aerobic modified medium. The calculations used to create FIGS. 7 and 8 include only considering the average relative transformation value 66 for a period of 2.5 hours or more in the protocol and 5 hours or less in the protocol. The average relative transformation value 66 for this time frame less than 0.5 and greater than 100 was discarded. ART blood values (defined herein as representative values of selected mean relative transformation values) were considered representative values of the remaining mean relative transformation values 66. This data was averaged in a set that matched the volume of blood measured (using multiple bins, these sets were divided into ranges of 2 ml blood volume, and in some cases, these bins were divided for analysis. ). The ART blood mean (Figure 7) and ART blood median (Figure 8) were then regressed to demonstrate a 98.1% correlation between ART blood values (mean and median) and blood volume. Along with the line, it was plotted against the corresponding blood volume value. Advantageously, this blood volume measurement method is used in clinical laboratories to provide the necessary feedback to laboratory staff, helping staff perform quality control, and using the blood culture system 11 Can be optimized.

7 References All references cited herein are to the same extent as if each individual publication or patent or patent document was incorporated herein by reference in its entirety for all purposes, Which is incorporated herein by reference in its entirety for all purposes.

8. Modifications Many modifications and variations of the present invention are possible without departing from the spirit and scope of the invention, as will be apparent to those skilled in the art. The specific embodiments described herein are merely examples, and the present invention is limited only by the language of the appended claims, and all such equivalents are included in such claims. And
Below, the preferable aspect of this invention is shown.
1. A method for determining the amount of blood in a blood culture in a container, comprising:
(A) for each individual measurement in a plurality of measurements of the biological state of the blood culture in the vessel, performed at a different time between the first time point and the second time point, Calculating a normalized relative value between (i) the individual measurements and (ii) the initial biological state of the blood culture measured at an initial time point, thereby obtaining a plurality of normalized relative values Obtaining step;
(B) with respect to individual predetermined constant intervals of a plurality of time points between the first time point and the second time point; Determining a first derivative of a normalized relative value for the measurement, thereby obtaining a plurality of rate transformation values, wherein the plurality of rate transformation values includes a plurality of sets of rate transformation values; Each of the individual sets of rate transformation values in the plurality of sets of rate transformation values is for a different set of successive time points between the first time point and the second time point;
(C) For each individual set of rate transformation values in the plurality of sets of rate transformation values, an average relative transformation as a representative value for each rate transformation value in the individual set of rate transformation values. Calculating a value, thereby calculating a plurality of average relative transformation values;
(D) determining the amount of the blood in the blood culture in the container based on a representative value of the plurality of average relative transformation values;
Wherein said container comprises a said blood culture fluidly sensor composition in fluid communication, said sensor composition, when exposed to CO ₂ shows the change in the properties, the presence of the sensor composition, Non-destructive to the blood culture and the initial biological state of the blood culture is:
Measuring the output of the sensor at an initial time point, thereby determining the initial biological state of the blood culture, and measuring the output of the sensor at different time points and using the output Measuring by a method comprising the step of calculating a normalized relative value.
2. The determining step (D) compares the representative value of the plurality of average relative transformation values with a lookup table that matches the representative value of the plurality of average relative transformation values to a blood volume. Determining the amount of blood in the blood culture in the container according to 1. The method described in 1.
3. (E) outputting the amount of blood in the blood culture in the container to a user interface device, monitor, computer readable storage medium, computer readable memory, or a local or remote computer system; The method according to 1., further comprising the step of displaying the amount of blood in the blood culture.
4). The first time point is one hour or more after the initial time point, and the second time point is four hours or more after the initial time point. The method described in 1.
5. The first time point is 1.5 to 3 hours after the initial time point, and the second time point is 4.5 to 5.5 hours after the initial time point. 1. The method described in 1.
6). A representative value of the rate transformation value in the first set of rate transformation values in the plurality of sets of rate transformation values is:
The geometric mean of each rate transformation value in the first set of rate transformation values;
An arithmetic average of the rate transformation values in the first set of rate transformation values;
The median value of the rate transformation values in the first set of rate transformation values, or
1. including the mode of rate transformation values in the first set of rate transformation values. The method described in 1.
7). The representative value of the plurality of average relative transformation values is:
A geometric average of the plurality of average relative transformation values;
An arithmetic average of the plurality of average relative transformation values;
Including a median value of the plurality of average relative transformation values or a mode value of the plurality of average relative transformation values. The method described in 1.
8). The measurement of the blood culture in the plurality of measurements of the biological state of the blood culture is performed at periodic time intervals between the first time point and the second time point, respectively. Features 1 The method described in 1.
9. 7. The periodic time interval is a certain amount of time between 1 minute and 20 minutes. The method described in 1.
10. 7. The periodic time interval is a certain amount of time between 5 minutes and 15 minutes. The method described in 1.
11. Each average relative transformation value in the plurality of average relative transformation values that is lower than the first threshold or higher than the second threshold is calculated before calculating the representative value of the plurality of average relative transformation values. Each average relative transformation value excluded from the plurality of average relative transformation values and excluded from the plurality of average relative transformation values is the plurality of average relative transformations used in the comparing step (D). 1. It does not affect the representative value of the formation value. The method described in 1.
12 The measurement is performed by monitoring one of a fluorescent output, a luminescent output, and a colorimetric output of a CO ₂ sensor in contact with the blood culture. The method described in 1.
13. 1 to 50,000 measurements of the biological state of the blood culture in the container are in the plurality of measurements of the biological state of the blood culture. . The method described in 1.
14 1 to 10,000 measurements of the biological state of the blood culture in the container in the plurality of measurements of the biological state of the blood culture. . The method described in 1.
15. 1 to 5,000 measurements of the biological state of the blood culture in the container are in the plurality of measurements of the biological state of the blood culture. . The method described in 1.
16. Each of the predetermined predetermined intervals of the plurality of time points of step (B) comprises a respective rate transformation value for a time point in a time window between the first time point and the second time point, wherein the time window Is a period of 20 minutes to 10 hours. The method described in 1.
17. Each of the respective predetermined regular intervals of the plurality of time points of step (B) includes the first time point and the second time point when the biological state of the blood culture in the container is measured. 1. It consists of rate transformation values for all time points in the time window between, and the time window time period is 20 minutes to 2 hours. The method described in 1.
18. Each of the respective predetermined regular intervals of the plurality of time points of step (B) includes the first time point and the second time point when the biological state of the blood culture in the container is measured. 1. It consists of rate transformation values for all time points in the time window between, the time window being a period of 30 minutes to 90 minutes. The method described in 1.
19. Each set of rate transformation values in the plurality of rate transformation values consists of 4 to 20 consecutive rate transformation values. The method described in 1.
20. Each set of rate transformation values in the plurality of rate transformation values consists of 5 to 15 consecutive rate transformation values. The method described in 1.
21. Among the plurality of average relative transformation values, there are 5 to 500 average relative transformation values. The method described in 1.
22. Among the plurality of average relative transformation values, there are 20 to 100 average relative transformation values. The method described in 1.
23. The amount of blood in the blood culture is 1 ml to 40 ml. The method described in 1.
24. The amount of blood in the blood culture is 2 ml to 10 ml. The method described in 1.
25. The compound comprises tris-4,7-diphenyl-1,10-phenanthroline ruthenium (II) salt, tris-2,2′-bipyridyl ruthenium (II) salt, 9,10-diphenylanthracene, and mixtures thereof. 11. at least one compound selected from the group, wherein the compound is monitored for changes in fluorescence. The method described in 1.
26. A blood volume determination apparatus comprising a processor and a memory connected to the processor, wherein the blood volume determination device determines the volume of blood in a blood culture in a container, the memory comprising:
A blood volume determination module,
(I) For each individual measurement in a plurality of measurements of the biological state of the blood culture in the container, performed at a different time between the first time point and the second time point, electronically sign for the step of i) calculating a normalized relative value between said individual measurements and (ii) an initial biological state of said blood culture, thereby obtaining a plurality of normalized relative values Command,
(Ii) the biology at each predetermined time interval of the plurality of time points for each of the predetermined time intervals of the plurality of time points between the first time point and the second time point; Electronically encoded instructions for the step of determining a first derivative of a normalized relative value for a measurement of a dynamic state, thereby obtaining a plurality of rate transformation values, wherein the plurality of rate transformation values are: A plurality of sets of rate transformation values, each of the individual sets of rate transformation values in the plurality of sets of rate transformation values being consecutive between the first time point and the second time point. Electronically encoded instructions for different sets of time points;
(Iii) For each individual set of rate transformation values in the plurality of sets of rate transformation values, an average relative transformation as a representative value for each rate transformation value in the individual set of rate transformation values. Electronically encoded instructions for calculating a value, thereby calculating a plurality of average relative transformation values;
(Iv) a blood volume determination comprising: electronically encoded instructions for determining a volume of blood in the blood culture in the container based on a representative value of the plurality of average relative transformation values. With modules,
The container includes a sensor composition in fluid communication with the blood culture, the sensor composition exhibiting a change in properties when exposed to CO ₂ , wherein the presence of the sensor composition is indicative of the blood culture. Non-destructive to the object and the initial biological state of the blood culture:
Measuring the output of the sensor at an initial time point, thereby determining the initial biological state of the blood culture, and measuring the output of the sensor at different time points and using the output A blood volume determination apparatus comprising: measuring a normalized relative value by a method.
27. The memory is
A lookup table including a match between (i) a first set of values for a representative value of a plurality of mean relative transformation values and (ii) a set of blood volumes, said first set of values A lookup table, wherein for each value relative to a representative value of a plurality of mean relative transformation values at, a corresponding blood volume is present in said blood volume set;
The instruction (iv) for the determining step compares the representative value of the plurality of average relative transformation values with a lookup table that matches the representative value of the plurality of average relative transformation values to a blood volume. 26. further comprising instructions for determining the amount of blood in the blood culture in the vessel thereby. The blood volume determination apparatus described in 1.
28. A computer readable medium storing a computer program executable by a computer to determine the amount of blood in a blood culture in a container, the computer program comprising:
A blood volume determination module,
(I) for individual measurements in multiple measurements of the biological state in the blood culture in the vessel measured at different times between a first time point and a second time point, Electronically for the step of (i) calculating a normalized relative value between said individual measurements and (ii) an initial biological state of said blood culture, thereby obtaining a plurality of normalized relative values Encoded instructions; and
(Ii) the biological at each predetermined fixed interval of the plurality of time points for each of the predetermined predetermined intervals of the plurality of time points between the first time point and the second time point; An electronically encoded instruction for determining a first derivative of a normalized relative value for the measurement of state, thereby obtaining a plurality of rate transformation values, wherein the plurality of rate transformation values are rate Including a plurality of sets of transformation values, each of the individual sets of rate transformation values in the plurality of sets of rate transformation values being a consecutive time point between the first time point and the second time point Instructions for different sets of
(Iii) For each individual set of rate transformation values in the plurality of sets of rate transformation values, an average relative transformation as a representative value for each rate transformation value in the individual set of rate transformation values. Electronically encoded instructions for calculating a value, thereby calculating a plurality of average relative transformation values;
(Iv) a blood volume comprising electronically encoded instructions for determining a volume of blood in the blood culture in the container based on a representative value of the plurality of average relative transformation values With a decision module
The container comprises a said blood culture fluidly sensor composition in fluid communication, said sensor composition, when exposed to CO ₂ shows a measurable change in a property, the presence of the sensor composition, Non-destructive to the blood culture and the initial biological state of the blood culture is:
Measuring the output of the sensor at an initial time point, thereby determining the initial biological state of the blood culture, and measuring the output of the sensor at different time points and using the output Measuring the normalized relative value by a method.
29. The computer program is
(A) (i) a look-up table including a match between a first set of values for a representative value of a plurality of average relative transformation values and (ii) a set of blood volumes, A lookup table, wherein for each value relative to a representative value of a plurality of average relative transformation values in one set, a corresponding blood volume is present in said blood volume set;
The electronically encoded instruction (iv) for the determining step matches the representative value of the plurality of average relative transformation values and the representative value of the plurality of average relative transformation values to a blood volume. And further comprising instructions for determining the amount of blood in the blood culture in the container. A computer-readable medium according to claim 1.
30. A method for determining the amount of blood in a blood culture in a container, comprising:
(A) obtaining a plurality of measurements of the blood culture in the container, each measurement in the plurality of measurements being performed at a different time point between a first time point and a second time point; ,
(B) the biological state at each of the predetermined time intervals of the plurality of time points for each of the predetermined time intervals of the plurality of time points between the first time point and the second time point; Determining a first derivative of the measurement of the plurality of rate transformation values, wherein the plurality of rate transformation values includes a plurality of sets of rate transformation values, wherein the rate transformation value Each of the individual sets of rate transformation values in the plurality of sets for a different set of successive time points between the first time point and the second time point;
(C) For each individual set of rate transformation values in the plurality of sets of rate transformation values, an average relative transformation as a representative value for each rate transformation value in the individual set of rate transformation values. Calculating a value, thereby calculating a plurality of average relative transformation values;
(D) determining the amount of blood in the blood culture in the container based on the representative value of the plurality of average relative transformation values;
The container includes a sensor composition in fluid communication with the blood culture, the sensor including a composition that exhibits a measurable change in properties when exposed to CO ₂ , and the presence of the sensor composition Is non-destructive to the blood culture and represents the initial biological state of the blood culture:
Measuring the output of the sensor at an initial time point, thereby determining the initial biological state of the blood culture, and measuring the output of the sensor at different time points and using the output Measuring by means of a method comprising: calculating a normalized relative value.
31. The determining step (D) compares the representative value of the plurality of average relative transformation values with a lookup table that matches the representative value of the plurality of average relative transformation values to a blood volume. 30. determining the amount of blood in the blood culture in the container according to 30. The method described in 1.
32. (E) outputting the amount of blood in the blood culture in the container to a user interface device, monitor, computer readable storage medium, computer readable memory, or a local or remote computer system; 30. further comprising displaying the amount of blood in the blood culture. The method described in 1.
33. 30. The first time point is one hour or more after the initial time point, and the second time point is four hours or more after the initial time point. The method described in 1.
34. The first time point is 1.5 to 3 hours after the initial time point, and the second time point is 4.5 to 5.5 hours after the initial time point. 30. The method described in 1.
35. A representative value of the rate transformation value in the first set of rate transformation values in the plurality of sets of rate transformation values is:
The geometric mean of each rate transformation value in the first set of rate transformation values;
An arithmetic average of the rate transformation values in the first set of rate transformation values;
30. comprising a median value of rate transformation values in the first set of rate transformation values, or a mode value of rate transformation values in the first set of rate transformation values. The method described in 1.
36.
The representative value of the plurality of average relative transformation values is:
A geometric average of the plurality of average relative transformation values;
An arithmetic average of the plurality of average relative transformation values;
30. A median value of the plurality of average relative transformation values or a mode value of the plurality of average relative transformation values. The method described in 1.
37. The measurement of the blood culture in the plurality of measurements of the biological state of the blood culture is performed at a periodic time interval between the first time point and the second time point. 30. The method described in 1.
38. 37. The periodic time interval is an amount of time from 1 minute to 20 minutes. The method described in 1.
39. 37. The periodic time interval is an amount of time between 5 minutes and 15 minutes. The method described in 1.
40. Each average relative transformation value in the plurality of average relative transformation values that is lower than the first threshold or higher than the second threshold is calculated before calculating the representative value of the plurality of average relative transformation values. Each average relative transformation value excluded from the plurality of average relative transformation values and excluded from the plurality of average relative transformation values is the plurality of average relative transformations used in the comparing step (D). 30. It does not affect the representative value of the formation value. The method described in 1.
41. 30. The initial biological state of the blood culture is determined by the fluorescence output of a sensor in contact with the blood culture. The method described in 1.
42. 41. The amount of fluorescence output of the sensor is affected by CO ₂ concentration. The method described in 1.
43. 30 to 10 to 50,000 measurements of the biological state of the blood culture in the container in the plurality of measurements of the biological state of the blood culture. . The method described in 1.
44. 30 to 100 to 10,000 measurements of the biological state of the blood culture in the vessel in the plurality of measurements of the biological state of the blood culture. . The method described in 1.
45. 30 to 5,000 measurements of the biological state of the blood culture in the container in the plurality of measurements of the biological state of the blood culture. . The method described in 1.
46. Each of the predetermined predetermined intervals of the plurality of time points of the step (B) consists of respective rate transformation values for the time points in the time window between the first time point and the second time point, 30. The window has a duration of 20 minutes to 10 hours. The method described in 1.
47. Each of the predetermined predetermined intervals of the plurality of time points of the step (B) is between the first time point and the second time point when the biological state of the blood culture in the container is measured. 30. The rate transformation values for all time points in the time window, wherein the time window has a duration of 20 minutes to 2 hours. The method described in 1.
48. Each of the predetermined predetermined intervals of the plurality of time points of the step (B) is between the first time point and the second time point when the biological state of the blood culture in the container is measured. 30. rate transformation values for all time points in the time window, wherein the time window has a duration of 30 minutes to 90 minutes. The method described in 1.
49. 30. Each set of rate transformation values in the plurality of rate transformation values comprises 4 to 20 consecutive rate transformation values. The method described in 1.
50. 30. Each set of rate transformation values in the plurality of rate transformation values comprises 5 to 15 consecutive rate transformation values. The method described in 1.
51. 30. The average relative transformation value of 5 to 500 exists among the plurality of average relative transformation values. The method described in 1.
52. 30. The average relative transformation value of 20 to 100 exists among the plurality of average relative transformation values. The method described in 1.
53. 30. The amount of blood in the blood culture is 1 ml to 40 ml. The method described in 1.
54. 30. The amount of blood in the blood culture is 2 to 10 ml. The method described in 1.

Claims (23)

A method for determining the amount of blood in a blood culture in a container, comprising:
(A) a first time point and were carried out at different times during the second time point, the individual in the measurement regarding CO ₂ and a plurality of measurements of the biological state of the blood culture in the vessel For each measurement, calculate a normalized relative value between (i) the individual measurement and (ii) the initial biological state of the blood culture measured at an initial time point, thereby Obtaining a plurality of normalized relative values for each of a plurality of predetermined time intervals ;
(B) with respect to individual predetermined constant intervals of a plurality of time points between the first time point and the second time point; Determining a first derivative of a normalized relative value for the measurement, thereby obtaining a plurality of rate transformation values, wherein the plurality of rate transformation values includes a plurality of sets of rate transformation values; Each of the individual sets of rate transformation values in the plurality of sets of rate transformation values is for a different set of successive time points between the first time point and the second time point;
(C) For each individual set of rate transformation values in the plurality of sets of rate transformation values, an average relative transformation as a representative value for each rate transformation value in the individual set of rate transformation values. Calculating a value, thereby calculating a plurality of average relative transformation values;
(D) determining the amount of the blood in the blood culture in the container based on a representative value of the plurality of average relative transformation values;
Wherein said container comprises a said blood culture fluidly sensor composition in fluid communication, said sensor composition, when exposed to CO ₂ shows the change in the properties, the presence of the sensor composition, Non-destructive to the blood culture, measuring the initial biological state of the blood culture, the output of a sensor at an initial time point, thereby the initial biology of the blood culture Measuring the output of the sensor at different points in time and calculating a normalized relative value using said output and measuring the output of the sensor at different times.   The determining step (D) compares the representative value of the plurality of average relative transformation values with a lookup table that matches the representative value of the plurality of average relative transformation values to a blood volume. The method of claim 1, comprising determining the amount of blood in the blood culture in the container. (E) outputting the amount of blood in the blood culture in the container to a user interface device, monitor, computer readable storage medium, computer readable memory, or a local or remote computer system; The method of claim 1, further comprising displaying the amount of blood in the blood culture. A representative value of the rate transformation value in the first set of rate transformation values in the plurality of sets of rate transformation values is:
The geometric mean of each rate transformation value in the first set of rate transformation values;
An arithmetic average of the rate transformation values in the first set of rate transformation values;
The median value of the rate transformation values in the first set of rate transformation values, or
The method of claim 1, comprising a mode value of rate transformation values in the first set of rate transformation values. The representative value of the plurality of average relative transformation values is:
A geometric average of the plurality of average relative transformation values;
An arithmetic average of the plurality of average relative transformation values;
The method of claim 1, comprising a median value of the plurality of average relative transformation values or a mode value of the plurality of average relative transformation values. Each average relative transformation value in the plurality of average relative transformation values that is lower than the first threshold or higher than the second threshold is calculated before calculating the representative value of the plurality of average relative transformation values. Each average relative transformation value excluded from the plurality of average relative transformation values and excluded from the plurality of average relative transformation values is the plurality of average relative transformations used in the comparing step (D). The method according to claim 1, wherein the representative value of the formation value is not affected. The measurement is performed by monitoring one of a fluorescent output, a luminescent output, and a colorimetric output of a CO ₂ sensor in contact with the blood culture. the method of.   Each of the predetermined predetermined intervals of the plurality of time points of step (B) comprises a respective rate transformation value for a time point in a time window between the first time point and the second time point, wherein the time window The method of claim 1, wherein is a period of 20 minutes to 10 hours.   Each of the respective predetermined regular intervals of the plurality of time points of step (B) includes the first time point and the second time point when the biological state of the blood culture in the container is measured. The method of claim 1, comprising rate transformation values for all time points in between time windows, wherein the time window time period is between 20 minutes and 2 hours.   Each of the respective predetermined regular intervals of the plurality of time points of step (B) includes the first time point and the second time point when the biological state of the blood culture in the container is measured. The method of claim 1, comprising rate transformation values for all time points in between time windows, wherein the time window time period is a period of 30 to 90 minutes.   The compound comprises tris-4,7-diphenyl-1,10-phenanthroline ruthenium (II) salt, tris-2,2′-bipyridyl ruthenium (II) salt, 9,10-diphenylanthracene, and mixtures thereof. 8. The method of claim 7, wherein the compound is at least one compound selected from the group and the compound is monitored for changes in fluorescence. A blood volume determination apparatus comprising a processor and a memory connected to the processor, wherein the blood volume determination device determines the volume of blood in a blood culture in a container, the memory comprising:
A blood volume determination module,
(I) a plurality of measurements of the biological state of the blood culture in the container at different times between a first time point and a second time point, each individual measurement in the measurement for CO ₂ For each of (i) the individual measurements and (ii) a normalized relative value between the initial biological state of the blood culture and thereby a plurality of predetermined constants Electronically encoded instructions for obtaining a plurality of normalized relative values for each of the time intervals ;
(Ii) the biological at each predetermined fixed interval of the plurality of time points for each of the predetermined predetermined intervals of the plurality of time points between the first time point and the second time point; An electronically encoded instruction for determining a first derivative of a normalized relative value for the measurement of state, thereby obtaining a plurality of rate transformation values, wherein the plurality of rate transformation values are rate Including a plurality of sets of transformation values, each of the individual sets of rate transformation values in the plurality of sets of rate transformation values being a consecutive time point between the first time point and the second time point Electronically encoded instructions for different sets of
(Iii) For each individual set of rate transformation values in the plurality of sets of rate transformation values, an average relative transformation as a representative value for each rate transformation value in the individual set of rate transformation values. Electronically encoded instructions for calculating a value, thereby calculating a plurality of average relative transformation values;
(Iv) a blood volume determination comprising: electronically encoded instructions for determining a volume of blood in the blood culture in the container based on a representative value of the plurality of average relative transformation values. With modules,
The container includes a sensor composition in fluid communication with the blood culture, the sensor composition exhibiting a change in properties when exposed to CO ₂ , wherein the presence of the sensor composition is indicative of the blood culture. Non-destructive to the object, measuring the initial biological state of the blood culture, the output of the sensor at an initial time point, thereby determining the initial biological state of the blood culture A blood volume determination device comprising: a step of determining and measuring a sensor output at different times and using the output to calculate a normalized relative value. The memory is
A lookup table including a match between (i) a first set of values for a representative value of a plurality of mean relative transformation values and (ii) a set of blood volumes, said first set of values A lookup table, wherein for each value relative to a representative value of a plurality of mean relative transformation values at, a corresponding blood volume is present in said blood volume set;
The instruction (iv) for the determining step compares the representative value of the plurality of average relative transformation values with a lookup table that matches the representative value of the plurality of average relative transformation values to a blood volume. 13. The blood volume determination device of claim 12, further comprising instructions for determining the volume of blood in the blood culture in the container. A computer readable medium storing a computer program executable by a computer to determine the amount of blood in a blood culture in a container, the computer program comprising:
A blood volume determination module,
(I) in the measured values for CO ₂ and a plurality of measurements of the biological state of the blood culture in the vessel is measured at different times during the first time point and the second point in time for each individual measurement values, (i) a normalized relative value between an initial biological state of the individual measurements and (ii) said blood cultures was calculated and thereby a plurality of normal Electronically encoded instructions for the step of obtaining a normalized relative value;
(Ii) the biological at each predetermined fixed interval of the plurality of time points for each of the predetermined predetermined intervals of the plurality of time points between the first time point and the second time point; Electronically encoded instructions for determining a first derivative of a normalized relative value for the measurement of a state, thereby obtaining a plurality of rate transformation values for each of a plurality of predetermined time intervals Wherein the plurality of rate transformation values includes a plurality of sets of rate transformation values, each of the individual sets of rate transformation values in the plurality of sets of rate transformation values being the first time point. Instructions for different sets of successive time points between and the second time point;
(Iii) For each individual set of rate transformation values in the plurality of sets of rate transformation values, an average relative transformation as a representative value for each rate transformation value in the individual set of rate transformation values. Electronically encoded instructions for calculating a value, thereby calculating a plurality of average relative transformation values;
(Iv) a blood volume comprising electronically encoded instructions for determining a volume of blood in the blood culture in the container based on a representative value of the plurality of average relative transformation values With a decision module
The container comprises a said blood culture fluidly sensor composition in fluid communication, said sensor composition, when exposed to CO ₂ shows a measurable change in a property, the presence of the sensor composition, Non-destructive to the blood culture, measuring the initial biological state of the blood culture, the output of a sensor at an initial time point, thereby the initial biology of the blood culture A computer readable medium comprising: determining a target state; and measuring a sensor output at different times and using the output to calculate a normalized relative value. The computer program is
(A) (i) a look-up table including a match between a first set of values for a representative value of a plurality of average relative transformation values and (ii) a set of blood volumes, A lookup table, wherein for each value relative to a representative value of a plurality of average relative transformation values in one set, a corresponding blood volume is present in said blood volume set;
The electronically encoded instruction (iv) for the determining step matches the representative value of the plurality of average relative transformation values and the representative value of the plurality of average relative transformation values to a blood volume. 15. The computer-readable medium of claim 14, further comprising instructions for comparing to a lookup table to determine thereby determining the amount of blood in the blood culture in the container. A method for determining the amount of blood in a blood culture in a container, comprising:
(A) a plurality of CO ₂ to obtain a measurement step of the blood culture in the vessel, each measurement in the plurality of measurements, the line physician at different times during the first time point and the second point in time Thereby providing a plurality of predetermined intervals of time ;
(B) the biological state at each of the predetermined time intervals of the plurality of time points for each of the predetermined time intervals of the plurality of time points between the first time point and the second time point; Determining a first derivative of the measurement of the plurality of rate transformation values, wherein the plurality of rate transformation values includes a plurality of sets of rate transformation values, wherein the rate transformation value Each of the individual sets of rate transformation values in the plurality of sets for a different set of successive time points between the first time point and the second time point;
(C) For each individual set of rate transformation values in the plurality of sets of rate transformation values, an average relative transformation as a representative value for each rate transformation value in the individual set of rate transformation values. Calculating a value, thereby calculating a plurality of average relative transformation values;
(D) determining the amount of blood in the blood culture in the container based on the representative value of the plurality of average relative transformation values;
The container includes a sensor composition in fluid communication with the blood culture, the sensor including a composition that exhibits a measurable change in properties when exposed to CO ₂ , and the presence of the sensor composition Is non-destructive to the blood culture and describes the initial biological state of the blood culture:
Measuring the output of the sensor at an initial time point, thereby determining the initial biological state of the blood culture, and measuring the output of the sensor at different time points and using the output Measuring by means of a method comprising: calculating a normalized relative value.   The determining step (D) compares the representative value of the plurality of average relative transformation values with a lookup table that matches the representative value of the plurality of average relative transformation values to a blood volume. 17. The method of claim 16, comprising determining the amount of blood in the blood culture in the container according to. (E) outputting the amount of blood in the blood culture in the container to a user interface device, monitor, computer readable storage medium, computer readable memory, or a local or remote computer system; The method of claim 16, further comprising displaying the amount of blood in the blood culture. A representative value of the rate transformation value in the first set of rate transformation values in the plurality of sets of rate transformation values is:
The geometric mean of each rate transformation value in the first set of rate transformation values;
An arithmetic average of the rate transformation values in the first set of rate transformation values;
17. The median of rate transformation values in the first set of rate transformation values, or the mode value of rate transformation values in the first set of rate transformation values. The method described. The representative value of the plurality of average relative transformation values is:
A geometric average of the plurality of average relative transformation values;
An arithmetic average of the plurality of average relative transformation values;
The method of claim 16, comprising a median value of the plurality of average relative transformation values, or a mode value of the plurality of average relative transformation values. Each average relative transformation value in the plurality of average relative transformation values that is lower than the first threshold or higher than the second threshold is calculated before calculating the representative value of the plurality of average relative transformation values. Each average relative transformation value excluded from the plurality of average relative transformation values and excluded from the plurality of average relative transformation values is the plurality of average relative transformations used in the comparing step (D). The method according to claim 16, wherein the representative value of the formation value is not affected.   The method of claim 16, wherein the initial biological state of the blood culture is determined by a fluorescence output of a sensor in contact with the blood culture. The amount of light output of the sensor A method according to claim 22, characterized in that influenced the CO ₂ concentration.

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