WO2014121035A1 - Determination of sample dilution in a calibrated analyte sensor - Google Patents

Determination of sample dilution in a calibrated analyte sensor

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Publication number
WO2014121035A1
WO2014121035A1 PCT/US2014/014081 US2014014081W WO2014121035A1 WO 2014121035 A1 WO2014121035 A1 WO 2014121035A1 US 2014014081 W US2014014081 W US 2014014081W WO 2014121035 A1 WO2014121035 A1 WO 2014121035A1
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WO
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Prior art keywords
signal
system
time
data
embodiments
Prior art date
Application number
PCT/US2014/014081
Other languages
French (fr)
Inventor
Randy Tompot
Michael S. ESTES
Michael Higgins
Original Assignee
Edwards Lifesciences, Llc
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1495Calibrating or testing of in-vivo probes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1486Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/6852Catheters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M2005/1401Functional features
    • A61M2005/1403Flushing or purging
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M2005/1401Functional features
    • A61M2005/1404Keep vein-open rate [KVO], i.e. low flow rate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/33Controlling, regulating or measuring
    • A61M2205/3368Temperature
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/70General characteristics of the apparatus with testing or calibration facilities
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2230/00Measuring parameters of the user
    • A61M2230/20Blood composition characteristics
    • A61M2230/201Glucose concentration

Abstract

A continuous analyte monitoring system is described herein providing signals related to the detection and monitoring of one or more analytes in vivo. More specifically, the system relates to determining dilution of a sample by a calibrant solution and rejection and optionally replacement of signals associated with dilution having a signal time- history similar to the undiluted signal of interest.

Description

DETERMINATION OF SAMPLE DILUTION IN A CALIBRATED ANALYTE

SENSOR

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Application No.

61/760,006, filed February 1, 2013, which is incorporated by reference herein.

Technical Field

[0002] A continuous analyte monitoring system is described herein providing signals related to the detection and monitoring of one or more analytes in vivo. More specifically, the system relates to determining dilution of a sample by a calibrant solution and rejection and/or replacement of signals associated with dilution having a signal time- history similar to the undiluted signal of interest.

BACKGROUND

[0003] Some analyte monitoring systems use cyclical draw and flush routines to alternately draw fluid up to a sensor assembly and then flush calibration solution over the sensor assembly. In some instances, the catheter or sensor becomes occluded and prevents an effective draw from occurring. This occlusion causes the system to fail to draw all or some of the blood that is intended for sampling. Still other instances may occur with essentially similar results. As a result, the sensor can be continuously bathed in calibration solution or the blood draw can be diluted with the calibration solution resulting in inaccurate measurements.

SUMMARY

[0004] The following is a summary of the apparatus, methods, and computer program products described herein.

[0005] An exemplary method for detecting dilution of a blood analyte sensor signal is provided. The method comprises receiving a signal time-history associated with a signal comprising calibrant-diluted data and undiluted data; identifying the undiluted data from the signal time-history; and identifying the calibrant-diluted data from the signal time-history.

[0006] In some embodiments, the method further comprises removing the calibrant-diluted data from the signal time-history; determining replacement data for replacing the calibrant-diluted data in the signal time-history; and reconstructing the signal time-history based on the undiluted data and the replacement data.

[0007] In some embodiments, the identifying step enables determination of an accurate concentration of the analyte in the blood sample.

[0008] In some embodiments, the calibrant-diluted data comprises a time- segment from the signal time -history below or above a threshold range, and wherein the undiluted data comprises a time-segment from the signal time-history within the threshold range.

[0009] In some embodiments, the identifying step is based on nested logic.

[0010] In some embodiments, the determining step comprises: accessing a model of the signal time-history of undiluted data; and determining the replacement data based on the undiluted data and the model.

[0011] In some embodiments, at least one of the identifying step or the reconstructing step is based on a system being used to measure a concentration of an analyte present in a circulatory system of a subject.

[0012] In some embodiments, at least one of the determining step or the reconstructing step is based on at least one of a least squares fitting model, an adaptive model, a statistical model, or a heuristic model.

[0013] In some embodiments, at least one of the determining step or the reconstructing step is based on whether a system is being calibrated or whether the system is being used to measure a concentration of an analyte in a solution.

[0014] In some embodiments, at least one of the identifying the diluted data from the signal time -history step or removing the diluted data from the signal time-history step comprises: determining a difference of the first signal and the second signal time -history; and in response to determining the difference exceeds a first threshold, dropping at least a portion of the first signal time-history from a data set.

[0015] In some embodiments, alone or in combination with any of the previous embodiments, an apparatus is provided for removing calibrant-diluted data from an intermittently calibrated blood analyte signal, the apparatus comprising: a memory; a processor; at least one module, executable by the processor, and configured to: receive a signal time-history associated with a signal comprising calibrant-diluted data and undiluted data; identify the undiluted data from the signal time -history; identify the calibrant-diluted data from the signal time -history.

[0016] In some embodiments, alone or in combination with any of the previous embodiments, the module is further configured to: remove the calibrant-diluted data from the signal time-history; determine replacement data for replacing the calibrant- diluted data in the signal time-history; and reconstruct the signal time-history based on the undiluted data and the replacement data.

[0017] In some embodiments, a computer program product for removing calibrant-diluted data from a signal, the computer program product comprising: a non- transitory computer-readable medium comprising a set of codes for causing a computer to: receive a signal time-history associated with a signal comprising calibrant-diluted data and undiluted data; identify the undiluted data from the signal time -history; and identify the calibrant-diluted data from the signal time-history.

[0018] In some embodiments, the set of codes further causes a computer to: remove the calibrant-diluted data from the signal time-history; determine replacement data for replacing the calibrant-diluted data in the signal time-history; and reconstruct the signal time-history based on the undiluted data and the replacement data.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Having thus described embodiments of the system in general terms, reference will now be made to the accompanying drawings, where: [0020] FIG. 1 shows an exemplary continuous analyte sensor system, in accordance with embodiments of the present system.

[0021] FIG. 2 is a flow chart showing components of the system of FIG. 1;

[0022] FIG. 3 shows a signal time -history example of a non-enzyme (blank electrode) signal in the presence of a blood sample corrupted by calibrant dilution;

[0023] FIG. 4 shows a signal time-history example of an enzyme (working electrode) signal, with blank electrode subtracted, in the presence of a blood sample corrupted by calibrant dilution;

[0024] FIG. 5 is a signal time -history example showing calculated estimated glucose values (EGVs) before and after application of the present method;

[0025] FIG. 6 is an exploded view of a portion of FIG. 5 showing in greater detail the dilution detection and replacement in accordance with some embodiments of the present system;

[0026] FIG. 7 is an exploded view of a portion of FIG. 5 showing in greater detail the dilution detection and replacement in accordance with some embodiments of the present system;

[0027] FIG. 8 shows a temperature signal time-history example of a temperature signal during calibration and measurement in accordance with some embodiments of the present system;

[0028] FIG. 9 shows an example of a non-enzyme blank electrode and enzyme working electrode signal response during a measurement cycle of an alternate embodiment of the present system;

[0029] FIG. 10 shows overlapping signal time-histories of a non-enzyme blank electrode and enzyme working electrode signal response during a measurement and calibration cycle of the alternate embodiment of the present system; [0030] FIG. 11 shows the difference of signal amplitudes of the signal time- histories of FIG. 10 represented as calculated estimated analyte concentrations;

[0031] FIG. 12 shows overlapping signal time-histories of a non-enzyme blank electrode and enzyme working electrode signal response during a measurement and calibration cycle with dilution events of the alternate embodiment of the present system;

[0032] FIG. 13 shows the difference of signal amplitudes of the signal time- histories of FIG. 12 represented as calculated estimated analyte concentrations;

[0033] FIG. 14 shows overlapping signal time-histories of a non-enzyme blank electrode and enzyme working electrode signal response during a measurement and calibration cycle with a dilution event of the alternate embodiment of the present system;

[0034] FIG. 15 shows the difference of signal amplitudes of the signal time- histories of FIG. 10 represented as calculated estimated analyte concentrations, with corrected value for the dilution event;

[0035] FIG. 16 depicts an exemplary calculation protocol for an embodiment of the present system.

DETAILED DESCRIPTION

[0036] Previous attempts at correcting inaccurate measurements from dilution events occurring in continuous analyte monitoring systems that intermittently calibrate the system involved waveform analysis of sensor waveforms f(e.g., r the signal time- history) from multiple electrodes, namely an enzyme containing electrode (e.g., working electrode or WE) and one with no-enzyme (e.g., blank electrode, BE). Dilution is established based in firstly on an appreciable change (>20%) in BE signal amplitude between cycles, and secondly by a corresponding appreciable change in estimated glucose value (EGV) exceeding a threshold. However, in practice the above approaches have not proven effective to reliable detection of less severe or less subtle instances of dilution events; namely, when the onset of dilution is gradual and/or intermittent during operation of the continuous analyte monitoring systems.

[0037] Embodiments of the present system and methods now may be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all, embodiments of the system are shown. Indeed, the system and methods may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure may satisfy applicable legal requirements. Like numbers refer to like elements throughout.

[0038] As used in the specification, and in the appended claims, the singular forms "a", "an", "the", include plural referents unless the context clearly dictates otherwise. The term "comprising" and variations thereof as used herein is used synonymously with the term "including" and variations thereof and are open, non- limiting terms.

[0039] With reference to FIG. 1, embodiments of the present disclosure include a blood analyte sensor system 10 that includes a monitor 12, a sensor assembly 14, a calibrant solution source 16 and a flow control system 18, as shown in FIG. 1. The system may also include other sensors, such as pressure sensors, temperature sensors, pH sensors, and the like. Notably, the present disclosure could also be employed with other analyte or blood parameter sensing systems that require drawing of blood or fluid samples from a patient. Blood, as used herein, should be construed broadly to include any body fluid with a tendency to occlude lumens of various body-access devices during sampling. The body access devices include blood access devices such as catheters, tubes, and stents. The flow control system 18 includes a flow controller 20, a monitor line 22, a sensor casing 24, an adapter 26, a sampling tube assembly 28 and a vascular access device 19. Generally, the flow control system 18 is configured to mediate flow of small volumes of the calibrant solution over the sensor assembly 14 and withdraw small volumes of samples of the blood from the patient for testing by the sensor assembly. [0042] The flow control system 18 in another embodiment is able to support the flush and draw pressures and volumes, and the high number of sampling cycles over a long multi-day indwell, needed for continuous analyte (glucose) monitoring, while avoiding the formation of thrombi that occur in conventional catheters by providing a small-diameter, smooth and relatively void free surface defining a lumen extending up to the sensor assembly 14. In another embodiment, the sampling tube assembly 28 may be employed with a range of existing catheter configurations by having the sampling tube assembly 28 sized and configured for coupling with a lumen of an existing catheter. In still other embodiments of the present disclosure, thrombus formation is inhibited by balancing the structure of various components of the flow control system 18 and operation of the flush and draw cycles by the flow controller 20.

[0043] The monitor 12 is connected in communication with the sensor assembly 14 through communication lines 36, which may be wires, and to the flow control system 18 through communication lines or wires 38, as shown in FIG. 1. In an embodiment, the monitor and the flow controller are integrated together. The communication lines 36, 38 could also represent wireless data communication such as cellular, RF, infrared or blue- tooth communication. Regardless, the monitor 12 includes some combination of hardware, software and/or firmware configured to record and display data reported by the sensor assembly 14. For example, the monitor may include processing and electronic storage for tracking and reporting blood glucose levels. In addition, the monitor 12 may be configured for automated control of various operations of other aspects of the sensor system 10. For example, the monitor 12 may be configured to operate the flow control system 18 to flush the sensor assembly 14 with calibration solution from calibrant solution source 16 and/or to draw samples of blood for testing by the sensor assembly. Also, the monitor 12 can be configured to calibrate the sensor assembly 14 based on the flush cycle.

[0044] In some embodiments, the analyte sensor is configured to reside within the catheter lumen. In some embodiments, the sensor is disposed within the catheter such the sensor does not protrude from the catheter orifice. In other embodiments, the sensor is disposed within the catheter such that at least a portion of the sensor protrudes from the catheter orifice. In still other embodiments, the sensor is configured to move between protruding and non-protruding configurations. The analyte sensor and vascular access device used in the sensor system 10 can be any types known in the art. For convenience, the vascular access device 12 will be referred to as a catheter herein. However, one skilled in the art appreciates that other vascular access devices can be used in place of a catheter.

[0045] In some embodiments, at least one electronics module (not shown) is included in the monitor 12, for controlling execution of various system functions, such as but not limited to system initiation, sensor calibration, movement of the flow controller 20 from one position to another, collecting and/or analyzing data, and the like. In other embodiments, the components and functions of the electronics module can be divided into two or more parts, such as between the local analyzer and remote analyzer. The monitor can be configured to accept digital and/or analog signals, as needed or desired. The components of the system 10 can be all solid state, for example.

[0046] While any number of flow controller configurations can be employed, for convenience of describing various aspects of the present disclosure, the flow controller 20 includes one or more valves and is configured to control fluid delivery to the subject and sample take-up (e.g., drawing blood back into the catheter and presenting flush and/or calibrant solution until at least the sensor's electroactive surfaces are contacted by the blood). In one exemplary embodiment, the flow controller 20 is a rotating pinch valve that has first and second positions. The valve can move between the two positions, for example, backward and forward, and thereby move fluids in and out of the catheter. In this manner, solution 16 can be moved from the reservoir 18, over electroactive surfaces of the sensor 14 and into the subject; and sample can be drawn up from the subject, to cover the electroactive surfaces of the sensor 14, and then pushed back into the subject, by movement of the valve between the first and second positions.

[0047] In some embodiments, the sensor 14 and one or all of the working electrodes, reference and/or counter electrodes, dwells within the lumen of the catheter 12. In one aspect, an internal calibration is performed where an infusion fluid (e.g., calibration solution 16) flows over the indwelling sensor 14 and is infused into the subject. Generally, analyte in the solution 16 can be measured when the sensor electroactive surfaces are in contact with the solution 16. In some embodiments, the measurements of the solution 16 can be used to calibrate the sensor 14. After calibration, the system is configured such that a sample (e.g., blood or other bodily fluid) contacts the sensor's electroactive surfaces (e.g., by drawing blood back into the catheter). When the sample contacts the electroactive surfaces, the sample's analyte concentration can be detected by the sensor 14. When a sample is drawn back, the sample can then be returned to the subject. In some embodiments, the sensor system 10 cycles between calibration (e.g., measurement of a reference calibration solution) and measurement (e.g., of a sample, such as blood, glucose concentration). In some embodiments, the system 10 continues operation in this cyclical manner, until the system 10 is either disconnected from the subject or turned off for a period of time (e.g., during movement of the subject from one location to another). For example, in one embodiment, the system 10 cycles between the calibration and measurement steps from about every 30 seconds or less to about every 2 hours or more. In another embodiment, the system 10 cycles between the calibration and measurement steps of from about every 2 minutes to about every 45 minutes. In still another embodiment, the system 10 cycles between the calibration and measurement steps from about every 1 minute to about every 10 minutes. In some embodiments, the user can adjust the time between steps. In some embodiments, the user can adjust the time between each step. In some embodiments, the system 10 can perform additional steps, such as but not limited to a flushing step, a keep vein open step (KVO), an extended infusion step, and the like. In some embodiments, the time is dependent upon sensors that detect a reference solution (e.g., calibration solution) and/or sample (e.g., blood) at the electroactive surfaces.

[0048] A variety of flow regulators 17can be used with the preferred embodiments, including but not limited to pinch valves, such as rotating pinch valves and linear pinch valves, cams and the like. In one exemplary embodiment, the flow regulator 17 is a pinch valve, supplied with the IV set and located on the tubing 22 adjacent to and below the drip chamber. In some embodiments, a flow regulator 17 controls the flow rate from the reservoir 18 to a flow controller 20. In some embodiments, a flow regulator is optional; and a flow controller 20 controls the flow rate (e.g., from the reservoir 18 to the catheter 14).

[0049] In some embodiments, a method for continuously measuring an analyte in an artery of a subject in vivo, and for detecting and correcting for dilution of the signal from the sensor 14 during the operation of the system 10, is provided. In this embodiment, the method includes the steps of coupling a continuous analyte sensor with an arterial catheter system applied to a subject, wherein the sensor is configured to generate an analyte-related signal associated with an analyte associated with the blood of the subject's vasculature, and wherein the arterial catheter system includes an arterial catheter, such that a sample of arterial blood contacts the sensor; and generating the analyte-related signal with the sensor. In some embodiments, the coupling step includes coupling the sensor to the arterial catheter, such as by inserting the sensor into a lumen of the arterial catheter. In some embodiments, the method includes a step of reinfusing the sample into the subject, such as by increasing the amount of pressure in the tubing 22. In preferred embodiments, the analyte-related signal is processed (e.g., calibrated, signal processed, modified, partially deleted, partially substituted) to provide an analyte value. In some embodiments, the analyte value is an estimated glucose value EGV (mg glucose/dL) presented on the monitor 12.

Detecting and Correcting Dilution - Signal Processing Methods

[0050] In one aspect, application of this disclosure will improve system measurement accuracy as measurements made against diluted samples will be detected and/or rejected with a higher frequency than currently available methods. Indeed, a particular advantage of the present disclosure is the early detection of the onset of dilution during operation of the system. Early detection of the onset of dilution will preserve system availability (e.g., "on-time" performance) as this condition may be communicated to a system user (e.g., via the monitor 12) who can then attempt to alleviate or adapt to the situation, for example, by addressing the primary cause, such as blockages in fluid delivery paths, clots, etc. The further utilization of a thermistor signal represents another independent and more direct means of detecting dilution and is discussed below.

[0051] Thus, in one aspect, an algorithm with the capacity to accurately detect sample dilution, in systems where biosensors are alternately exposed to different fluids, such as blood and a saline-based, calibrant-containing solution (calibrant and/or flush solution) is provided. As used herein, "diluted samples" are those that have some level of mixing between the fluids at the time of measurement, and are inclusive of a blood sample that contains an appreciable quantity of calibrant and/or saline solution. Diluted samples provide "diluted signals" or "calibrant-diluted signals" from the sensor. Where measurements (or signals) are intended to be analyzed, compared, or used in calculations against each fluid in isolation, significant dilution typically results in inaccurate system readings.

[0052] Thus, in one aspect, the disclosed algorithm described herein determines sample dilution by an independent analysis of multiple sensor waveforms. Sensor waveforms (or "signal time-history" or "signal time-histories") are generated by the sampling rate and detected voltage or current and can be depicted as signal output verses time plots. An independent analysis of multiple sensor waveforms based on known or predicted physiological rates of change of analyte concentration in a species can be used to deduce if a dilution event is occurring. For example, in a dual electrode (WE and BE) sensor continuous glucose measurement system, the present algorithm can apply nested logic to determine whether or not a particular blood sample is diluted, that being typically a sample taken over a given time period commensurate with the system sampling and/or calibration cycle. Given that the non-enzyme (BE) electrode has a consistent baseline response when exposed to blood, the first criteria of the nested logic method comprises detecting signaling dilution as a deviation from the known or predicted physiological response. Excluding, as an example, such extraneous effects such as temperature and sensor sensitivity drift, when the BE electrode is exposed to a non- diluted sample, the BE electrode's signal waveform amplitude will not change in the presence of such a blood sample, typically not over the lifetime of the sensor. However, when the BE electrode's signal waveform amplitude drops by an appreciable percentage (e.g., >2 , > 5%, or >10 ), this is a signal indicating possible dilution, for example, as depicted in FIG. 3, where signal time -history 101 has a deflection 103 of its amplitude, e.g., signal current, shown. The individual measurement of a diluted sample present at the electrode of the sensor is not in and of itself inaccurate; however, the result as reported by the system can be "misrepresented" in that the assumption is made that the sample was undiluted at the time of measurement. Thus, during operation of the system, the signal generated by the sensor's WE and BE comprises at least one of a first signal substantially sensitive to a concentration of an analyte in a calibrant solution and substantially sensitive to a concentration of an analyte in a blood sample, and a second signal substantially insensitive to a calibrant solution and substantially insensitive to the concentration of the analyte in the blood sample, respectively.

[0053] If an aberrant drop in the BE electrode amplitude is detected, the second criteria of the nested logic to establish dilution is to determine whether the corresponding WE electrode signal amplitude has changed correspondingly to that of the measured glucose concentration of the calibrant, which can be higher or lower than the glucose concentration of the subject. Thus, as depicted in FIG. 4, where the calibrant glucose concentration is higher than that of the sampled blood, it can be observed that the enzyme signal amplitudes increases concomitantly with the drop in BE electrode's amplitude, due to the contribution of the calibrant glucose to the overall measurement signal (e.g., deflection 103 of FIG. 3 corresponds to that of deflection 105 of FIG. 4.

[0054] A third criterion of the nested logic towards establishing sample dilution is that a change in WE signal amplitude toward calibration is likely non-physiological in nature. For example, given a maximum allowable physiological rate-of-change for blood glucose, such as 1.0 mg/dL/minute, a non-physiological change would be one where the change in WE signal amplitude between measurements divided by the time between them would exceed this threshold. For instance, for measurements separated by 5 minutes, a change of +/- 5.0 mg/dL would be a maximum, beyond which the observed change in signal amplitude would be considered non-physiological, and would satisfy the triple nested conditions established for detecting blood sample dilution.

[0055] FIGs. 5, 6, and 7 depict a demonstration of the present method applied to clinical data on a subject. Figure 5 compares estimated glucose values (EGVs) as calculated from raw clinical waveform data both before application of the present method (Control; open circles) and after application of the present method (Closed circles, with a calculated line).

[0056] FIG. 6 and FIG. 7 are exploded views of portions 6 and 7, (the first and second halves of FIG. 5) respectively, and demonstrate that the present method has identified several cases of dilution, as indicated by empty circles where the present method has rejected that measurement (e.g., and/or not calculated an EGV).

[0057] With reference now to FIG. 8, another embodiment of the present disclosure is provided, whereby the combination of the above-described nested logic method with corresponding analysis of an independent thermistor signal is employed. In this embodiment, the temperature of the sample is taken during analyte measurement (the "measurement phase") of the continuous analyte monitoring system's cycle. To the extent that drawn and then measured blood is essentially at or near the subject's body temperature, while the flush and/or calibrant solution is at or near room temperature, the difference between these temperatures is sufficiently appreciable (up to about 10 degrees Celsius +/- 2) and can provide a predictable temperature-related signal that will be representative of a temperature change during "normal" system operation, for example, as the different fluids are alternatively or intermittently presented to the BE and WE electrodes. During alternatively or intermittently presented fluids to the BE and WE electrodes corresponding signals are obtained and subsequent EGV's measured. However, dilution events during operation of the system will necessarily cause this predicted differential of temperature to fall outside of a predicted threshold value or range as depicted in FIG. 8 (boxes indicated with arrows and marked as "calibration" and "blood draw" where the calibration temperature is significantly lower than that of the blood draw.) Thus, detecting a temperature signal corresponding to a portion of the system cycle related to blood draw that falls below the threshold value or range (as indicated by the box, e.g., having a temperature range of lower than about 33.4), as for example, depicted in FIG. 8, would be interpreted by the module as a further indication of or a validation of establishing dilution of the blood sample. The system can be configured to make adjustments to the signals or calculated data based on the current body temperature of the subject, for example, via an external temperature monitor or by manual input of the operator, to compensate for fever or hypothermia conditions.

[0058] In addition, a temperature signal corresponding to the temperature of the solution presented to the WE during measurement mode can be used to further establish or verify a dilution event.

[0059] Whereas previously mentioned, "on-time" is a continuous analyte sensor system property related to the ratio of displayable values to the total number of measured values. Thus, an on-time of 80% means that, on average, 8 out of every 10 measurements results in a displayed value that is considered accurate by the system's electronic module. Maximizing on-time performance while remaining accurate is a key performance requirement of any measurement system. Hence, in addition to the above method, an alternate method, independent of the previously described method is provided for, among other things, maximizing the "on-time" performance of a continuous analyte sensor system.

[0060] As mentioned above, the BE electrode responds differently to blood than to an aqueous calibration solution and is generally insensitive to glucose concentration, it can be used to indicate dilution. Applying some of the criteria from above also allows the BE electrode to provide for the method of correcting for dilution on the WE electrode, and/or removing dilution signal and/or replacing dilution signal for display or storage.

[0061] Thus, at least one aspect of this alternate embodiment is the advantageous improvement of on-time performance of a continuous analyte monitoring system by correcting and/or replacing values derived from dilution-related events, rather than dropping these values and/or not presenting values to the end user. [0062] By way of example, an alternate embodiment presently disclosed is provided. For purposes of explanation, and for calculating a "dilution factor," a frame of reference can be used. Thus, as depicted in FIG. 9a typical, undiluted signals (e.g., current "I") from a continuous analyte monitoring system are shown, depicted in signal time -history or waveform form, the BE electrode (BE waveform 203) and WE electrode (WE waveform 201) during an exemplary complete measurement cycle. The first half of the measurement cycle is the calibration phase where the WE and BE electrodes are producing steady-state currents I4 and Ii, respectively. The second half of the measurement cycle is the measurement phase where the WE and BE electrodes are producing steady-state currents I3 and I2, respectively. In FIG. 9a, it is depicted that I4 during the calibration phase is greater than I3 during the measurement phase, thus, the blood glucose concentration is less than the glucose concentration of the calibration solution. In alternate embodiments, the concentration of the calibration solution can be greater than the blood glucose concentration. In FIG. 9b, it is depicted that the relationship between the BE signal is linear between blood and the calibration solution, however, itdoes not have to be purely linear, but can be non-linear, such as 2nd order and can still achieve similar results. In other words, so long as the BE signal increases from that from calibration solution to blood (e.g., .having a non-zero first derivative), the presently disclosed method is applicable.

[0063] As previously described above, the BE electrode response to blood is generally consistent during the calibration/measurement cycles during use of the system. During operation of the system, both the blood temperature and sensor drift (change in sensitivity) are very slow. The magnitude of I2 therefore, can be used, advantageously, because as the temperature changes this value also changes. An improved reference is the difference between the BE electrode signal I2 during the measurement cycle and the BE electrode signal Ii during the calibration cycle. As blood temperature changes, both (I2 and Ii) signals change similarly.

[0064] Thus, when no dilution is present, the difference (I2-I1) of the BE signal during the measurement cycle is a maximum value, which can represent a threshold value. In the presence of dilution, where blood is diluted by the calibration solution, the mixture produces a difference signal that is proportional to the ratio of dilution and, therefore less than the maximum or threshold value. FIG. 10 depicts the cycle of FIG. 9 repeated a plurality of cycles for a non-changing or constant blood glucose concentration. FIG. 11 depicts the constant EGV values determined from the plurality of cycles to represent un-diluted measurements.

[0065] With reference to FIGs. 12 and 13, is depicted a plurality of measurement cycles where one or more dilution events (e.g., at measurement cycles 5 and 6). In this aspect, the BE amplitude signal difference, (I2-I1) is a useful parameter for determining dilution events. The BE signal difference correlates to a change in the WE electrode during the measurement phase and the direction of the change must be towards the WE signal measured during the calibration phase (for a calibrant concentration higher than the blood glucose measured. For example, this relationship can be used to accurately determine the extent or amount of dilution. Thus, a 40% decrease in the BE electrode signal difference (I2-I1) would indicate a mixture of 60% blood and 40% calibration solution presented to the WE during the measurement cycle. If the concentration of the calibration solution is 200 mg/dL and the blood glucose concentration at a given measurement cycle is 150 mg/dL, a 60/40% mixture would result in an estimated glucose value (EGV) of 170 mg/dL as the WE signal would increase essentially linearly between the true signal of 150 and 200 mg/dL. This is represented in FIG. 13, where the calibrant- diluted measurement cycles deviate from the correctly estimated EGVs. Understanding the concentration of the calibration solution, the calculated blood glucose value, and that the sample was 40% diluted, an actual value can be calculated and/or replace the calibrant-diluted EGV using the presently disclosed method.

[0066] Thus, with reference to FIGs. 14 and 15, which show a signal time-history of a BE and WE with a dilution event at time interval 12:35 and an EGV representation showing the uncorrected and corrected EVGs, respectively, as described herein. The method is shown in a form suitable for programing in FIG. 16, which provides at least one calculation protocol suitable for a computer module or program adaptable to a continuous analyte monitoring system. In one aspect, the analyte is glucose.

[0067] Embodiments described herein are also directed to systems, methods, and computer program products for detecting calibrant-diluted signals and optionally, correcting and/or replacing the EGVs calculated therefrom for display to a user. It is further claimed that the present approach can be applied to analyte signals measured by transducers used to measure analyte concentration in-vivo or in-vitro using intermittent calibration by calibrant solutions. As used herein, "data" and "data-points" may be used interchangeably.

[0068] The system described herein mitigates the effects of dilution on a glucose measurement system. The signal (e.g., a current or voltage signal) described herein enables determination of an analyte concentration in a solution (e.g., the glucose concentration in a blood sample or any other fluid).

[0069] In one aspect, one or more modules can be employed to facilitate the method. Thus, a first module of the system can determine a dilution event by taking the difference of the WE and BE and comparing the difference value with a threshold value. A dilution factor can be calulated based on an ideal calibration and measurement cycle.

[0070] The second module of the system processes the signal with diluted data to improve the accuracy of the diluted EGV original signal without dilution. This can be accomplished, for example, by interpolating between non-diluted data-points. Depending on the time -history selected from the signal, different interpolation techniques are used. The phases associated with the signal may comprise only a measurement phase (when glucose concentration is being measured).

[0071] Any of the features described herein with respect to a particular process flow are also applicable to any other process flow. In accordance with embodiments described herein, the term "module" with respect to a system may refer to a hardware component of the system, a software component of the system, or a component of the system that includes both hardware and software. As used herein, a module may include one or more modules, where each module may reside in separate pieces of hardware or software.

[0072] Although many embodiments of the present system have just been described above, the present system may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Also, it will be understood that, where possible, any of the advantages, features, functions, devices, and/or operational aspects of any of the embodiments of the present system described and/or contemplated herein may be included in any of the other embodiments of the present system described and/or contemplated herein, and/or vice versa. In addition, where possible, any terms expressed in the singular form herein are meant to also include the plural form and/or vice versa, unless explicitly stated otherwise. Accordingly, the terms "a" and/or "an" shall mean "one or more," even though the phrase "one or more" is also used herein. Like numbers refer to like elements throughout.

[0073] As will be appreciated by one of ordinary skill in the art in view of this disclosure, the present system may include and/or be embodied as an apparatus (including, for example, a system, machine, device, computer program product, and/or the like), as a method (including, for example, a method, computer-implemented process, and/or the like), or as any combination of the foregoing. Accordingly, embodiments of the present system may take the form of an entirely method embodiment, an entirely software embodiment (including firmware, resident software, micro-code, stored procedures in a database, etc.), an entirely hardware embodiment, or an embodiment combining method, software, and hardware aspects that may generally be referred to herein as a "system." Furthermore, embodiments of the present system may take the form of a computer program product that includes a computer-readable storage medium having one or more computer-executable program code portions stored therein. As used herein, a processor, which may include one or more processors, may be "configured to" perform a certain function in a variety of ways, including, for example, by having one or more general-purpose circuits perform the function by executing one or more computer- executable program code portions embodied in a computer-readable medium, and/or by having one or more application-specific circuits perform the function.

[0074] It will be understood that any suitable computer-readable medium may be utilized. The computer-readable medium may include, but is not limited to, a non- transitory computer-readable medium, such as a tangible electronic, magnetic, optical, electromagnetic, infrared, and/or semiconductor system, device, and/or other apparatus. For example, in some embodiments, the non-transitory computer-readable medium includes a tangible medium such as a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable readonly memory (EPROM or Flash memory), a compact disc read-only memory (CD- ROM), and/or some other tangible optical and/or magnetic storage device. In other embodiments of the present system, however, the computer-readable medium may be transitory, such as, for example, a propagation signal including computer-executable program code portions embodied therein.

[0075] One or more computer-executable program code portions for carrying out operations of the present system may include object-oriented, scripted, and/or unscripted programming languages, such as, for example, Java, Perl, Smalltalk, C++, SAS, SQL, Python, Objective C, JavaScript, and/or the like. In some embodiments, the one or more computer-executable program code portions for carrying out operations of embodiments of the present system are written in conventional procedural programming languages, such as the "C" programming languages and/or similar programming languages. The computer program code may alternatively or additionally be written in one or more multi-paradigm programming languages.

[0076] Some embodiments of the present system are described herein with reference to flowchart illustrations and/or block diagrams of apparatus and/or methods. It will be understood that each block included in the flowchart illustrations and/or block diagrams, and/or combinations of blocks included in the flowchart illustrations and/or block diagrams, may be implemented by one or more computer-executable program code portions. These one or more computer-executable program code portions may be provided to a processor of a general purpose computer, special purpose computer, and/or some other programmable data processing apparatus in order to produce a particular machine, such that the one or more computer-executable program code portions, which execute via the processor of the computer and/or other programmable data processing apparatus, create mechanisms for implementing the steps and/or functions represented by the flowchart(s) and/or block diagram block(s).

[0077] The one or more computer-executable program code portions may be stored in a transitory and/or non-transitory computer-readable medium (e.g., a memory, etc.) that can direct, instruct, and/or cause a computer and/or other programmable data processing apparatus to function in a particular manner, such that the computer- executable program code portions stored in the computer-readable medium produce an article of manufacture including instruction mechanisms which implement the steps and/or functions specified in the flowchart(s) and/or block diagram block(s).

[0078] The one or more computer-executable program code portions may also be loaded onto a computer and/or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer and/or other programmable apparatus. In some embodiments, this produces a computer-implemented process such that the one or more computer-executable program code portions which execute on the computer and/or other programmable apparatus provide operational steps to implement the steps specified in the flowchart(s) and/or the functions specified in the block diagram block(s). Alternatively, computer-implemented steps may be combined with, and/or replaced with, operator- and/or human-implemented steps in order to carry out an embodiment of the present system.

[0079] While certain exemplary embodiments have been described and shown in the accompanying drawings, it is to be understood that such embodiments are merely illustrative of and not restrictive on the broad system, and that this system not be limited to the specific constructions and arrangements shown and described, since various other changes, combinations, omissions, modifications and substitutions, in addition to those set forth in the above paragraphs, are possible. Those skilled in the art will appreciate that various adaptations, modifications, and combinations of the just described embodiments can be configured without departing from the scope and spirit of the system. Therefore, it is to be understood that, within the scope of the appended claims, the system may be practiced other than as specifically described herein.

Claims

WHAT IS CLAIMED IS:
1. A method for detecting dilution of a blood analyte sensor signal, the method comprising:
receiving a signal time-history associated with a signal comprising calibrant-diluted data and undiluted data;
identifying the undiluted data from the signal time-history; and identifying the calibrant-diluted data from the signal time-history.
2. The method of claim 1, further comprising:
removing the calibrant-diluted data from the signal time-history;
determining replacement data for replacing the calibrant-diluted data in the signal time-history; and
reconstructing the signal time -history based on the undiluted data and the replacement data.
3. The method of claim 1, wherein the signal comprises at least one of first signal substantially sensitive to a concentration of an analyte in a calibrant solution and substantially sensitive to a concentration of an analyte in a blood sample, and a second signal substantially insensitive to a calibrant solution and substantially insensitive to the concentration of the analyte in the blood sample.
4. The method of claim 2, wherein the identifying step enables determination of an accurate concentration of the analyte in the blood sample.
5. The method of claim 2, wherein the analyte comprises glucose.
6. The method of claim 1, wherein the calibrant-diluted data comprises a time- segment from the signal time-history below or above a threshold range, and wherein the undiluted data comprises a time-segment from the signal time -history within the threshold range.
7. The method of claim 1, wherein the identifying step is based on nested logic.
8. The method of claim 1, wherein at least one of the identifying step or the reconstructing step is based on a system being used to measure a concentration of an analyte present in a circulatory system of a subject.
9. The method of claim 2, wherein the determining step comprises:
accessing a model of the signal time-history of undiluted data; and
determining the replacement data based on the undiluted data and the model.
10. The method of claim 9, wherein the model comprises substantially undiluted data.
11. The method of claim 9, wherein the model is based on a previous, undiluted signal time-history associated with the signal.
12. The method of claim 9, wherein the model is generated in substantially real-time.
13. The method of claim 9, wherein the model is generated based on a minimization model such that a normalized difference between a parameter of the model and a parameter of the undiluted data is more than or equal to a predetermined threshold.
14. The method of claim 1, wherein the receiving step comprises:
measuring a quantity associated with the blood sample;
converting the measured quantity to the signal.
15. The method of claim 14, wherein the quantity comprises a voltage or current.
16. The method of claim 14, wherein the signal comprises at least one of a first signal substantially sensitive to a calibration solution and substantially sensitive to an analyte concentration associated with a blood sample, and a second signal substantially insensitive to the calibrant solution and substantially insensitive to the analyte concentration associated with the blood sample.
17. The method of claim 14, wherein at least one of the identifying the calibrant- diluted data from the signal time-history step or removing the calibrant-diluted data from the signal time-history step comprises: determining a difference of the first signal and the second signal time -history; and
in response to determining the difference exceeds a first threshold, dropping at least a portion of the first signal time-history from a data set.
18. The method of claim 17, wherein the rate of change is based on a predetermined value.
19. The method of claim 1, wherein the signal is generated by one or more electronic circuits.
20. An apparatus for removing calibrant-diluted data from an intermittently calibrated blood analyte signal, the apparatus comprising:
a memory;
a processor;
at least one module, executable by the processor, and configured to:
receive a signal time -history associated with a signal comprising calibrant-diluted data and undiluted data;
identify the undiluted data from the signal time-history; and identify the calibrant-diluted data from the signal time-history.
21. The apparatus of claim 22, wherein the module is further configured to:
remove the calibrant-diluted data from the signal time-history;
determine replacement data for replacing the calibrant-diluted data in the signal time-history; and
reconstruct the signal time-history based on the undiluted data and the replacement data.
22. A computer program product for removing calibrant-diluted data from a signal, the computer program product comprising:
a non-transitory computer-readable medium comprising a set of codes for causing a computer to:
receive a signal time-history associated with a signal comprising calibrant-diluted data and undiluted data;
identify the undiluted data from the signal time-history; and identify the calibrant-diluted data from the signal time-history.
23. The computer program product of claim 24, wherein the set of codes further causing a computer to:
remove the calibrant-diluted data from the signal time-history;
determine replacement data for replacing the calibrant-diluted data in the signal time-history; and
reconstruct the signal time-history based on the undiluted data and the replacement data.
PCT/US2014/014081 2013-02-01 2014-01-31 Determination of sample dilution in a calibrated analyte sensor WO2014121035A1 (en)

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