WO2014036175A1 - Modifying a sensitivity value to adjust for lag between in vivo sensor analyte values and an in vitro reference analyte value - Google Patents

Modifying a sensitivity value to adjust for lag between in vivo sensor analyte values and an in vitro reference analyte value Download PDF

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Publication number
WO2014036175A1
WO2014036175A1 PCT/US2013/057140 US2013057140W WO2014036175A1 WO 2014036175 A1 WO2014036175 A1 WO 2014036175A1 US 2013057140 W US2013057140 W US 2013057140W WO 2014036175 A1 WO2014036175 A1 WO 2014036175A1
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analyte
vivo
level
analyte level
reference
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PCT/US2013/057140
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French (fr)
Inventor
Mark Kent Sloan
Kenneth J. Doniger
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Abbott Diabetes Care Inc.
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Priority to US201261695168P priority Critical
Priority to US61/695,168 priority
Application filed by Abbott Diabetes Care Inc. filed Critical Abbott Diabetes Care Inc.
Publication of WO2014036175A1 publication Critical patent/WO2014036175A1/en

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    • 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
    • A61B5/1495Calibrating or testing of in-vivo probes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2560/00Constructional details of operational features of apparatus; Accessories for medical measuring apparatus
    • A61B2560/02Operational features
    • A61B2560/0223Operational features of calibration, e.g. protocols for calibrating sensors

Abstract

Methods, devices, systems, and kits are provided that determine user in vivo analyte levels over time based upon analyte data being received from an in vivo analyte sensor; display analyte levels over time based on the in vivo analyte levels; determine a current reference analyte level based on received reference analyte data from a reference analyte device; compare a current in vivo analyte level with the current reference analyte level; adjust a next displayed analyte level to the current reference analyte level; and transition subsequently displayed analyte levels toward subsequently determined in vivo analyte levels by an incremental amount over a predetermined time period. Numerous additional aspects are disclosed.

Description

MODIFYING A SENSITIVITY VALUE TO ADJUST FOR LAG BETWEEN IN VIVO SENSOR ANALYTE VALUES AND AN IN VITRO REFERENCE ANALYTE VALUE

PRIORITY

[0001] This application claims priority to U.S. Provisional Patent Application Serial No.

61/695,168, filed on August 30, 2012, entitled "Modifying a Sensitivity Value to Adjust For Lag Between In Vivo Sensor Analyte Values and an In Vitro Reference Analyte Value", the disclosure of which is incorporated herein by reference in its entirety for all purposes.

BACKGROUND

[0002] The detection of the concentration level of glucose or other analytes in certain individuals is vitally important to their health. For example, the monitoring of glucose levels is particularly important to individuals with diabetes or pre-diabetes. People with diabetes may need to monitor their glucose levels to determine when medication (e.g., insulin) is needed to reduce their glucose levels or when additional glucose is needed.

[0003] Devices have been developed for continuous and automatic in vivo monitoring of analyte characteristics, such as glucose levels, in bodily fluids such as in the blood stream or in interstitial fluid. Some of these analyte measuring devices are configured so that at least a portion of the devices are positioned below a skin surface of a user, e.g., in a blood vessel or in the subcutaneous tissue of a user.

SUMMARY

[0004] A user may obtain a reference analyte measurement to check the results of an in vivo monitoring system. In certain instances however, the values from the two may not match exactly even though the difference is not large enough to present any clinical risk. Even so, the un-matched values may unnecessarily alarm or confuse a user. The methods, devices, and systems of the present invention address this issue. In certain embodiments, if an in vivo analyte measurement value does not exactly match a contemporaneously- obtained reference measurement value but does not pose a clinical risk to the user, the in vivo analyte measurement value is modified to more closely approximate the reference measurement value. The modified value is then displayed on a display device in place of the in vivo analyte measurement value.

[0005] Clinical risk refers to the possibility that a user may rely on a measured

physiological value to the detriment of the patient. In the present context, clinical risk refers to the possibility that the difference between the reference value and the in vivo analyte measurement value is large enough to suggest that a user should take responsive action that might actually harm the patient. For example, if a current in vivo analyte measurement value indicates that immediate medical attention is required and a contemporaneous reference value from an in vitro test indicates otherwise, the difference is large enough to present a clinical risk and the in vivo analyte measurement value would not be adjusted.

[0006] In some embodiments, the present invention provides method implemented using one or more computer processors. The method includes determining user in vivo analyte levels over time based upon analyte data being received from an in vivo analyte sensor; displaying analyte levels over time based on the in vivo analyte levels; determining a current reference analyte level based on received reference analyte data from a reference analyte device; comparing a current in vivo analyte level with the current reference analyte level; adjusting a next displayed analyte level to the current reference analyte level; and transitioning subsequently displayed analyte levels toward subsequently determined in vivo analyte levels by an incremental amount over a predetermined time period.

[0007] In some other embodiments, the present invention provides an apparatus. The apparatus includes a user interface; one or more processors coupled to the user interface and memory storing instructions. The instructions, when executed by the one or more processors, cause the one or more processors to determine user in vivo analyte levels over time based upon analyte data being received from an in vivo analyte sensor; display analyte levels over time based on the in vivo analyte levels; determine a current reference analyte level based on received reference analyte data from a reference analyte device; compare a current in vivo analyte level with the current reference analyte level; adjust a next displayed analyte level to the current reference analyte level; and transition subsequently displayed analyte levels toward subsequently determined in vivo analyte levels by an incremental amount over a predetermined time period. [0008] In yet other embodiments, the present invention provides integrated analyte monitoring assemblies. The integrated analyte monitoring assemblies include an analyte sensor for transcutaneous positioning through a skin layer and maintained in fluid contact with an interstitial fluid under the skin layer during a predetermined time period, the analyte sensor having a proximal portion and a distal portion; and sensor electronics coupled to the analyte sensor. The sensor electronics include a circuit board having a conductive layer and a sensor antenna disposed on the conductive layer; one or more electrical contacts provided on the circuit board and coupled with the proximal portion of the analyte sensor to maintain continuous electrical communication; and a data processing component provided on the circuit board and in signal communication with the analyte sensor. The data processing component is configured to execute one or more routines for processing signals received from the analyte sensor. The data processing component is configured to control the transmission of data associated with the processed signals received from the analyte sensor to a remote location using the sensor antenna in response to a request signal received from the remote location. The data processing component includes a memory storing instructions. The instructions, when executed by the data processing component, cause the data processing component to determine user in vivo analyte levels over time based upon analyte data being received from an in vivo analyte sensor; display analyte levels over time based on the in vivo analyte levels; determine a current reference analyte level based on received reference analyte data from a reference analyte device; compare a current in vivo analyte level with the current reference analyte level; adjust a next displayed analyte level to the current reference analyte level; and transition subsequently displayed analyte levels toward subsequently determined in vivo analyte levels by an incremental amount over a predetermined time period.

[0009] Numerous other aspects and embodiments are provided. These other features and aspects of the present invention will become more fully apparent from the following detailed description, the appended claims, and the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 depicts a data monitoring and management system such as, for example, an analyte (e.g., glucose) monitoring system in accordance with some embodiments of the present invention.

[0011] FIG. 2 is a block diagram of a receiver/monitor unit such as that shown in FIG. 1 in accordance with some embodiments of the present invention.

[0012] FIG. 3 is a graph depicting a reference analyte measurement and sensor analyte levels according to some embodiments of the present invention.

[0013] FIG. 4 is a graph depicting a displayed reference analyte measurement and modified analyte levels displayed to a user according to some embodiments of the present invention.

[0014] FIG. 5 is a graph depicting a displayed reference analyte measurement and modified analyte levels displayed to a user according to some embodiments of the present invention.

[0015] FIG. 6 is a graph depicting a displayed reference analyte measurement and predicted analyte levels displayed to a user according to some embodiments of the present invention.

[0016] FIG. 7 is a flow chart illustrating an example method according to some

embodiments of the present invention.

DETAILED DESCRIPTION

[0017] The present invention provides methods and apparatus to avoid user confusion from the display of an in vivo monitored analyte concentration level that may appear to be inconsistent with a reference analyte concentration level. Systems used to continuously determine and display analyte concentration of a user or patient may use an analyte sensor positioned below the user's skin and in contact with an interstitial fluid. While the analyte concentration (e.g., blood glucose level) of interest may be accurately determined by such systems, in some cases there may be a time delay or lag between a change in the analyte concentration in the user's blood and a corresponding change in the user's interstitial fluid. Thus, for example, a conventional continuous glucose monitor that samples interstitial fluid in vivo may temporarily display a different blood glucose concentration than a reference blood glucose meter that uses an in vitro blood sample (e.g., from a finger prick) if the blood glucose concentration is changing at the time the blood sample was taken. Although not clinically significant, the apparent inconsistency due to the time delay may cause concern and/or confusion for the user. The user may lose confidence in the accuracy of the continuous glucose monitor.

[0018] A used herein, the term "clinically significant" is intended to refer to a measured amount or degree of a physiological characteristic that represents a medical event or condition that requires attention or treatment. As stated above, the term "clinical risk" is intended to refer to the possibility that the difference between the reference value and the in vivo analyte measurement value is large enough to suggest that a user should take responsive action that might actually harm the patient. Since the difference between the reference value and the in vivo analyte measurement value contemplated in the present invention is not clinically significant, the present invention avoids any clinical risk.

[0019] However, to overcome the problem of a user being confused or unduly concerned by the difference, in some embodiments, the present invention uses the reference analyte level to effectively time-shift the displayed analyte level determined based on data from the continuous in vivo sensor. In other words, for example, since it is known that a continuous in vivo glucose monitor will eventually display the same value as a reference in vitro blood glucose meter, the value displayed by the continuous glucose monitor is immediately set equal to the value from the reference blood glucose meter. Then, over a period of time, the value displayed by the continuous glucose monitor may be

incrementally adjusted back to the value being currently determined by the continuous glucose monitor. In some embodiments, the value displayed may be held constant until the value being currently determined by the continuous glucose monitor matches the displayed value. At the point in time when the displayed and determined values match, the value displayed going forward may be the determined value from the in vivo glucose monitor. The invention may be applied to any analyte level determination system that may lag an instantaneous reference measurement system. The present invention also provides numerous additional embodiments.

[0020] Turning now to FIG. 1, a data monitoring and management system such as, for example, an analyte {e.g., glucose) monitoring system in accordance with some embodiments of the present disclosure is depicted. Embodiments of the subject disclosure are described primarily with respect to glucose monitoring devices and systems but the present invention may be applied to other analytes and analyte characteristics. For example, other analytes that may be monitored include, but are not limited to, acetyl choline, amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase (e.g., CK- MB), creatine, DNA, fructosamine, glutamine, growth hormones, hormones, ketones, lactate, peroxide, prostate-specific antigen, prothrombin, RNA, thyroid stimulating hormone, and troponin. The concentration of drugs, such as, for example, antibiotics (e.g., gentamicin, vancomycin, and the like), digitoxin, digoxin, drugs of abuse, theophylline, and warfarin, may also be monitored. In those embodiments that monitor more than one analyte, the analytes may be monitored at the same or different times.

[0021] Referring to FIG. 1 , the analyte monitoring system 100 includes a sensor 101 , a data processing unit (e.g., sensor electronics) 102 connectable to the sensor 101 , and a receiver unit 104 which is configured to communicate with the data processing unit 102 via a communication link 103. In aspects of the present disclosure, the sensor 101 and the data processing unit (sensor electronics) 102 may be configured as a single integrated assembly 1 10. In some embodiments, the integrated sensor and sensor electronics assembly 1 10 may be configured as an on-body patch device. In such embodiments, the on-body patch device may be configured for, for example, radio frequency identification (RFID) or radio frequency (RF) communication with a reader device/receiver unit, and/or an insulin pump.

[0022] In some embodiments, the receiver unit 104 may be further configured to transmit data to a data processing terminal 105 to evaluate or otherwise process or format data received by the receiver unit 104. The data processing terminal 105 may be configured to receive data directly from the data processing unit 102 via a communication link which may optionally be configured for bi-directional communication. Further, the data processing unit 102 may include a transmitter or a transceiver to transmit and/or receive data to and/or from the receiver unit 104 or the data processing terminal 105. Only one sensor 101 , data processing unit 102 and data processing terminal 105 are shown in the embodiment of the analyte monitoring system 100 illustrated in FIG. 1. However, it will be appreciated by one of ordinary skill in the art that the analyte monitoring system 100 may include more than one sensor 101 and/or more than one data processing unit 102, and/or more than one data processing terminal 105. [0023] The analyte monitoring system 100 may be a continuous monitoring system, or semi-continuous, or a discrete monitoring system. In a multi-component environment, each component may be configured to be uniquely identified by one or more of the other components in the system so that communication conflicts may be readily resolved between the various components within the analyte monitoring system 100. For example, unique IDs, communication channels, and the like, may be used.

[0024] In some embodiments, the sensor 101 is physically positioned in or on the body of a user whose analyte level is being monitored. The data processing unit 102 is coupleable to the sensor 101 so that both devices are positioned in or on the user's body, with at least a portion of the analyte sensor 101 positioned transcutaneously. The data processing unit 102 in some embodiments may include a portion of the sensor 101 (proximal section of the sensor in electrical communication with the data processing unit 102) which is encapsulated within or on the printed circuit board of the data processing unit 102 with, for example, potting material or other protective material. The data processing unit 102 performs data processing functions, where such functions may include but are not limited to, filtering and encoding of data signals, each of which corresponds to a sampled analyte level of the user, for transmission to the receiver unit 104 via the communication link 103. In some embodiments, the sensor 101 or the data processing unit 102 or a combined sensor/data processing unit may be wholly implantable under the skin layer of the user.

[0025] In operation, the receiver unit 104 in some embodiments is configured to

synchronize with the data processing unit 102 to uniquely identify the data processing unit 102, based on, for example, an identification information of the data processing unit 102, and thereafter, to periodically receive signals transmitted from the data processing unit 102 associated with the monitored analyte levels detected by the sensor 101. That is, when operating in the continuous glucose monitoring (CGM) mode, the receiver unit 104 in some embodiments is configured to automatically receive data related to the analyte level of a user from the analyte sensor/sensor electronics when the communication link (e.g., RF range) is maintained between these components.

[0026] Referring again to FIG. 1, the data processing terminal 105 may include a personal computer, a portable data processing device or computers such as a laptop computer or a handheld device (e.g., personal digital assistants (PDAs, tablets, phablets, etc.),

-Ί- communication devices such as a cellular phone or a Smartphone (e.g., a multimedia and Internet-enabled mobile phone such as an iPhone®, an Android® device, a Blackberry® device, a Palm® device such as Palm Pre®, Treo®, or similar phone), mp3 player, pager, and the like), drug delivery device, insulin pump, each of which may be configured for data communication with the receiver via a wired or a wireless connection. Additionally, the data processing terminal 105 may further be connected to a data network (not shown).

[0027] The data processing terminal 105 may include an infusion device such as an insulin infusion pump or the like, which may be configured to administer insulin to patients, and which may be configured to communicate with the primary receiver unit 104 for receiving, among others, the measured analyte level. Alternatively, the receiver unit 104 may be configured to integrate an infusion device therein so that the receiver unit 104 is configured to administer insulin (or other appropriate drug) therapy to patients, for example, for administering and modifying basal profiles, as well as for determining appropriate boluses for administration based on, among others, the detected analyte levels received from the data processing unit 102. An infusion device may be an external device or an internal device (wholly implantable in a user). An insulin bolus calculator may be operatively coupled to the receiver unit 104 to determine an insulin dose that is required based upon the analyte data received from the sensor device/electronics.

[0028] In some embodiments, the data processing terminal 105, which may include an insulin pump, may be configured to receive the analyte signals from the data processing unit 102, and thus, incorporate the functions of the receiver unit 104 including data processing for managing the patient's insulin therapy and analyte monitoring. In some embodiments, the communication link 103 as well as one or more of the other

communication interfaces shown in FIG. 1 may use one or more of an RF communication protocol, an infrared communication protocol, a Bluetooth® enabled communication protocol, an 802.1 lx wireless communication protocol, or an equivalent wireless communication protocol which would allow secure, wireless communication of several units (for example, per HIPAA requirements) while avoiding potential data collision and interference.

[0029] The various processes described above including the processes operating in the software application execution environment in the analyte monitoring system including the on-body patch device, the reader device, data processing module and/or the remote terminal performing one or more routines described above may be embodied as computer programs developed using an object oriented language that allows the modeling of complex systems with modular objects to create abstractions that are representative of real world, physical objects and their interrelationships. The software (e.g., instructions) required to carry out the inventive process, which may be stored in a memory or storage device of the storage unit of the various components of the analyte monitoring system described above in conjunction with the drawing, including the on-body patch device, the reader device, the data processing module, various described communication devices, or the remote terminal may be developed by a person of ordinary skill in the art and may include one or more computer program products.

[0030] In some embodiments, an apparatus for bi-directional communication with an analyte monitoring system may comprise a storage device having stored therein one or more routines, a processing unit operatively coupled to the storage device and configured to retrieve the stored one or more routines for execution, a data transmission component operatively coupled to the processing unit and configured to transmit data based at least in part on the one or more routines executed by the processing unit, and a data reception component operatively coupled to the processing unit and configured to receive analyte related data from a remote location and to store the received analyte related data in the storage device for retransmission, wherein the data transmission component is

programmed to transmit a query to a remote location, and further wherein the data reception component receives the analyte related data from the remote location.

[0031] FIG. 2 is a block diagram of a receiver/monitor unit or insulin pump such as that shown in FIG. 1 in accordance with some embodiments. The receiver unit 104 (FIG. 1) includes one or more of: a blood glucose test strip interface 201 , an RF receiver 202, an input 203, a temperature monitor section 204, and a clock 205, each of which is operatively coupled to a processing and storage section 207. In some embodiments, a receiver unit, such as primary receiver unit 104 also includes a power supply 206 operatively coupled to a power conversion and monitoring section 208. Further, the power conversion and monitoring section 208 is also coupled to the receiver processor 207. Moreover, also shown are a receiver serial communication section 209, and an output 210, each operatively coupled to the processing and storage unit 207. The receiver may include user input and/or interface components or may be free of user input and/or interface components.

[0032] In one aspect, the RF receiver 202 is configured to communicate, via the

communication link 103 (FIG. 1) with the data processing unit (sensor electronics) 102, to receive encoded data from the data processing unit 102 for, among others, signal mixing, demodulation, and other data processing. The input 203 of the primary receiver unit 104 is configured to allow the user to enter information into the primary receiver unit 104 as needed. In one aspect, the input 203 may include keys of a keypad, a touch-sensitive screen, and/or a voice-activated input command unit, and the like. The temperature monitor section 204 may be configured to provide temperature information of the primary receiver unit 104 to the processing and control section 207, while the clock 205 provides, among others, real time or clock information to the processing and storage section 207.

[0033] Each of the various components of the primary receiver unit 104 shown in FIG. 2 is powered by the power supply 206 (or other power supply) which, in some embodiments, includes a battery. Furthermore, the power conversion and monitoring section 208 is configured to monitor the power usage by the various components in the primary receiver unit 104 for effective power management and may alert the user, for example, in the event of power usage which renders the primary receiver unit 104 in sub-optimal operating conditions. The serial communication section 209 in the primary receiver unit 104 is configured to provide a bi-directional communication path from the testing and/or manufacturing equipment for, among others, initialization, testing, and configuration of the primary receiver unit 104.

[0034] Serial communication section 209 can also be used to upload data to a computer, such as functionality related data. The communication link with an external device (not shown) can be made, for example, by cable (such as USB or serial cable), infrared (IR) or RF link. The output/display 210 of the primary receiver unit 104 is configured to provide, among others, a graphical user interface (GUI), and may include a liquid crystal display (LCD) for displaying information. Additionally, the output/display 210 may also include an integrated speaker for outputting audible signals as well as to provide vibration output as commonly found in handheld electronic devices, such as mobile telephones, pagers, etc. In some embodiments, the primary receiver unit 104 also includes an electro-luminescent lamp configured to provide backlighting to the output 210 for output visual display in dark ambient surroundings.

[0035] Referring back to FIG. 2, the primary receiver unit 104 may also include a storage section such as a programmable, non-volatile memory device as part of the processor 207, or provided separately in the receiver unit 104, operatively coupled to the processor 207. The processor 207 may be configured to perform Manchester decoding (or other protocol(s)) as well as error detection and correction upon the encoded data received from the data processing unit 102 via the communication link 103.

[0036] In some embodiments, the data processing unit 102 and/or the receiver unit 104, and/or the data processing terminal/infusion section 105 may be configured to receive the blood glucose value wirelessly over a communication link from, for example, a blood glucose meter. In some embodiments, a user manipulating or using the analyte monitoring system 100 (FIG. 1) may manually input the blood glucose value using, for example, a user interface (for example, a keyboard, keypad, voice commands, and the like) incorporated in the one or more of the data processing unit 102, the receiver unit 104, or the data processing terminal/infusion section 105.

[0037] In some embodiments, the present methods, apparatuses, and systems transition the sensitivity value used to calculate an analyte sensor level that is equal to the reference analyte measurement for display on the receiver unit 104. According to some

embodiments, the continuous analyte monitoring system described above allows a user to provide a reference analyte measurement to calibrate the sensor signal to determine the user's sensor analyte level. For purposes of calibration, the user can obtain the reference analyte measurement by, e.g., using a finger stick to sample in vitro blood with a test strip. The results of the finger stick can be manually entered by the user into the receiver unit 104. Alternately, the primary receiver unit may include a test strip port operatively coupled thereto, which automatically determines the results of the finger stick. During the period of calibration, the receiver unit 104 in the continuous analyte monitoring system can optionally concurrently display both the reference analyte measurement and the sensor analyte level determined using a subcutaneous analyte sensor. Sensor analyte

measurements can differ from the corresponding reference analyte measurements used to calibrate the sensor due to a lag in interstitial analyte levels verses blood analyte levels.

Consequently, displaying a sensor analyte level that is different than the reference analyte measurement can lead to user confusion and a lack of confidence in the continuous analyte monitoring system. Thus, the present methods, apparatuses, and systems allow the sensitivity value used to calibrate the analyte sensor data to transition such that the displayed analyte sensor level is equal to the reference analyte measurement even if the actual current sensor analyte level differs from the reference value, thereby increasing user confidence in the continuous analyte monitoring system. The variance between an actual sensor analyte level and its reference value is a non-clinical risk variance. In other words, the difference between the two is a clinically acceptable amount.

[0038] In an instance when the user's blood analyte level is not changing, the determination of sensor sensitivity S(0) can be determined by the receiver unit 104 as a ratio of the reference analyte measurement (e.g., referencevalue(Q)) and the raw sensor analyte data

(e.g., sensordata(0)), as seen below in Equation 1.

s(Q) = referencevalue(0) J }

sensordata(0)

[0039] Using the determined sensor sensitivity value S(0), the primary receiver unit 104 can determine the sensor analyte level (e.g., sensorvalue(0)) as follows.

sensorvalue(0) = S(0) sensordata(0) (Equation 2)

[0040] However, when the user's blood analyte level is changing (e.g., increasing or decreasing), then the primary receiver unit 104 takes into account the rate of change of the blood analyte level using a time derivative of sensor data and a time constant T in determining the sensor sensitivity S(T).

S(T) = referencevaluei ) ^ ^

sensordata(T) sensordata(T) = sensordata(Q) + T ' ^ sensor(^ata) (Equation 4)

dt \t=0

[0041] An expression analogous to Equation 2 can be used by the receiver unit 104 to determine the sensor value from the sensor data that takes into account the rate of change. The sensordata(T) is the best estimate, by the receiver unit 104, of the sensor analyte level including an estimate of the affect of changing blood analyte levels. Note that when the user's blood analyte is not changing, sensordata(Q) is the same as the sensor data(T). If the newly determined sensitivity S( ) is used to determine the blood analyte level of the user from analyte sensor data, then the reference analyte measurement and analyte level value may not be equal when displayed using the output/display 210. This can be a consequence of a lag between the analyte level in the interstitial fluid versus in the blood. One such example is graphically illustrated in FIG. 3, when the user's blood glucose concentration (mg/dL) is rising over a particular time period (e.g., several minutes). As seen in FIG. 3, a reference analyte measurement 302 of the user's blood analyte level is obtained at around minute 3 to calibrate the analyte sensor, and yields a measurement of 200 mg/dL.

However, the sensor analyte level 304, which is displayed and stored by the receiver unit 104 of FIG. 1, as determined from the analyte sensor at the same time is around 160 mg/dL, and is noticeably less than the reference analyte measurement 302. This apparent disagreement is confusing, and concurrently displaying the reference analyte measurement 302 and the analyte sensor level 304 to the user could lead to a lack of user confidence in the system. The receiver unit 104 can also store the determined analyte level 304 for use in other data processing.

[0042] In some embodiments, an analyte sensor measurement from a second in vivo device may be used as the reference measurement. For example, the reference measurement, instead of being an in vitro test strip finger stick measurement, may be taken from a single measurement at a specific time by a CGM system that utilizes a calibrated analyte sensor, wherein the sensor measurement is determined based on a predetermined calibration factor and does not require user calibration over the lifetime of the sensor. Such systems and pre-calibrated sensors are described in more detail in, among others, for example, U.S. patent application no. 12/714,439 filed February 26, 2010, the disclosure of which is incorporated herein by reference for all purposes.

[0043] According to some embodiments, the present methods, apparatuses, and systems provide methods to transition the sensitivity value used to calculate the analyte sensor level to equal the reference analyte measurement for display purposes. For example, the sensitivity applied by the primary receiver unit 104, of FIG. 1, could smoothly transition from S(0) to S(T) over a 10 minute period, and display an analyte sensor level that matches the reference analyte measurement that will provide the user with increased confidence in the analyte monitoring system. It is understood that the value 10 minutes is used as an example, and that other values such as 5, 15, 20, 30 minutes, or for example, any time periods, e.g. that are integer multiples of the time between measuring analyte sensor levels, could be used. Mathematically, the transition may be expressed as follows.

Starting when a reference analyte measurement is obtained at t = 0, then

For (0 < t < 10), S(t) = - S(0) + ~ S(T) (Equation 5); and

For (t > 10), S(t) = 5(7) (Equation 6).

[0044] FIG. 4 is a graphical illustration of the above expression, as applied to the same data obtained in FIG. 3. As seen in FIG. 4, the reference analyte measurement 402 is obtained at minute 3 (i.e., t = 0) with a value of 200 mg/dL and at the same time, the displayed sensor analyte level 404 of 160 mg/dL is adjusted by the primary receiver unit 104 using sensitivity S(t) (i.e., Equation 5) to yield a value equivalent to that of the reference analyte measurement 402, e.g., 200 mg/dL, which can then be displayed to a user. Then, the sensitivity S(t) is used to calculate the displayed sensor analyte level 404 for 0 < t < 10, minutes 3 to 12 (408). After 10 minutes the sensitivity S(t) transitions back (410) and S( ) (i.e., Equation 6) is used to display the sensor analyte level 404. During the time period of 0 < t < 10 the receiver unit 104 can still determine the analyte level using S( ) and store this value in memory for purposes of data processing, although the actual sensor analyte level 406 is not displayed to the user during 0 < t < 10. At the end of the time period of 0 < t < 10 the interstitial analyte level has caught up to the lag with the blood analyte level at the beginning of the time period, and thus the transition back to displaying the analyte sensor level is smooth.

[0045] According to some embodiments, the present methods, apparatuses, and systems can monitor the rate of change of the analyte level to determine when to start the transition from S(0) to S(T). Turning to FIG. 5, based upon the received reference analyte measurement 502, the receiver unit 104 can determine a rate of change of the analyte level. The receiver unit 104 can compare the determined rate of change to a threshold level and if the rate of change is less than the threshold, then the receiver unit 104 can use sensitivity S(0) to determine the displayed sensor analyte level. However, as seen in the example of FIG. 5, if the receiver unit 104 determines that the rate of change meets or exceeds the threshold value, then the receiver unit 104 can transition the sensitivity used in determining the displayed sensor analyte level 504 using S( ) according to Equations 5 and 6 above. In this particular example, the receiver unit 104 uses S( ) to calculate the displayed sensor analyte level 504 from minutes 3 to 21 in the graph (508). Then the receiver unit 104 incrementally decreases the displayed analyte level from minutes 23 to 33 (510), until the displayed sensor analyte level (504) is also the stored sensor analyte level 506.

[0046] In addition, with reference to FIG. 6, the present methods, apparatuses, and systems can refine the estimate of sensordata(T) and sensor sensitivity S(Y) as additional sensor data become available using, for example, a least squares fitting of past and present analyte data to determine sensor signal slope at t = 0. The present methods, apparatuses, and systems can update the sensordata(T) at each minute after the receipt of the reference measurement until the transition to S(T) is completed. In other words, at time t = 0 when the reference measurement 602 is made, a determination of sensor sensitivity can be implemented as follows. Namely, S(0) can be calculated using Equation 1 and S( ) can be calculated using Equation 3. As more data arrives, sensordata(T) can be recalculated and so then can S( ). The sensitivity values through the transition, S(t), can then be calculated according to Equations 5 and 6.

[0047] A predicted sensitivity Sp(0) can also be determined at t = 0 using the least squares fit of the past and present analyte sensor data using Equation 7.

refer encevalue( ) (Equation y)

predicteddata (0)

[0048] It should be noted that the time constant, T, in Equation 5, the transition length from S(0) to S( ), and the number of minutes over which S(T) is updated, can be mutually independent of one another. The predicteddata(0) can include the predicted analyte level (606) each minute from t=0 to t=6 (i.e., minutes 15-21). The predicted sensitivity Sp(0) can be used to determine predicted analyte values (sensor analyte level 604) from, e.g., t=0 to t=6, which can then be displayed to the user, using the following: sensorvaluep (t) (Equation 8).

Figure imgf000017_0001

[0049] Then from, e.g., t=7 to t=10 (i.e., minutes 22-25), only the predicted sensitivity determined for t=7 is used in determining sensor analyte levels using the following: (Equation 9).

Figure imgf000017_0002

The actual sensor analyte level can also be determined and stored by the receiver device.

[0050] FIG. 7 is a flow chart illustrating a method 700 for adjusting displayed analyte values to compensate for lag between continuous in vivo sensor analyte levels and a reference analyte in vitro measurement. In some embodiments, a receiver unit 104 can receive a stream of analyte data related to analyte levels of a user from a continuous in vivo analyte sensor 101. The analyte data can be received via wired or wireless transmission from an on-body analyte sensor device worn by the user, or from a repeater unit that is in wired or wireless communication with the on-body analyte sensor device. For example, the repeater device can be worn on the belt of the user and can store analyte data received from the on-body sensor device. The analyte sensor data can be sent to the receiver unit 104 at predetermined intervals or only upon request from the receiver unit 104. The receiver unit 104 can include a portable analyte meter, a laptop computer, a smart phone, a personal computer, a personal digital assistant, etc. Moreover, the receiver unit 104 can be a user device or a healthcare provider device.

[0051] The analyte level over time of the user can be determined based on the analyte data received from the analyte sensor device (702). The analyte level over time of the user can be determined directly upon receipt of the analyte data, or the receiver unit 104 can wait to determine the analyte levels until a predetermined time. In addition, the analyte levels of the user can be displayed to the user by the receiver unit 104 (704). For example, the analyte levels can be displayed in textual or graphical trend line form by using a graphical user interface of the output/display 210 operatively coupled to the receiver unit 104, and/or the analyte level can be displayed to the user in audible form using an audio unit which may be included in output/display 210 operatively coupled to the receiver unit 104.

[0052] The receiver unit 104 can also receive reference analyte data related to a reference analyte measurement (e.g., made in vitro) of the user. In some embodiments, the reference analyte data can be obtained using a blood glucose test strip, and then entered by the user into the receiver device. In addition, the receiver unit 104 can include a blood analyte strip port operatively coupled thereto, and can automatically receive the reference analyte data from a test strip coupled to the test strip port. A reference analyte measurement can thus be determined by the receiver unit 104 based upon the received reference analyte data (706).

[0053] Based on a comparison of the determined reference analyte measurement and the determined analyte level (708), the receiver unit 104 can determine if the difference between the reference analyte measurement and the analyte level is clinically significant and therefore presents a clinical risk (710). For example, if the difference is larger than a predefined amount (e.g., approximately 10%), the receiver unit 104 may decide that an error condition exists. Other values may be used. In some embodiments, the receiver unit 104 may determine a threshold based on historical data wherein the receiver unit 104 deems that the difference between the reference analyte measurement and the in vivo analyte level could present a clinical risk if the difference is greater than the threshold amount. The historical data may include a record of a range of prior differences between reference analyte measurements and the in vivo analyte levels.

[0054] If it is determined that the difference between the reference analyte measurement and the in vivo analyte level could present a clinical risk, the displayed analyte levels are not adjusted (712). An alarm may be triggered and the receiver unit 104 may indicate to the user that there appears to be an error condition. A message to seek medical advice from a healthcare provider may be presented. In some embodiments, the receiver unit 104 may request that the user confirm the reference analyte level, for example, where the user provided the data or a potentially defective test strip was used.

[0055] If it is determined that the difference between the reference analyte measurement and the in vivo analyte level do not present a clinical risk, then the receiver unit 104 can adjust the next analyte level to be displayed to match the reference analyte measurement (714). In some embodiments, both the adjusted analyte level of the user and the reference analyte measurement may be concurrently displayed as the same value for a moment in time. Displaying the analyte level and the reference analyte measurement as the same value can provide ease of use, at least since displaying the reference analyte measurement and the analyte level that is modified to match the reference analyte measurement may impart less confusion when viewed by the user.

[0056] After adjusting the next analyte level to be displayed, in some embodiments, the receiver unit 104 can incrementally adjust subsequent analyte levels to be displayed back to the analyte levels being determined from the in vivo sensor data (716). The adjustments may be made by a predetermined amount over a predetermined time period. For example, the incremental adjustment of the modified displayed analyte level of the user can include a linear adjustment, an exponential adjustment, a random adjustment, a logarithmic adjustment, a parabolic adjustment, a polynomial adjustment, or any combination of these adjustments. In other words, the shape of a curve that represents the incremental changes over time from the reference analyte level to the in vivo analyte levels can be linear, exponential, random, logarithmic, parabolic, polynomial or any combination of these curve shapes. Thus, the transition from displaying the reference analyte level to the in vivo analyte levels can be described as a linear transition, an exponential transition, a random transition, a logarithmic transition, a parabolic transition, a polynomial transition, or any combination of these types of transitions. In some embodiments, the adjustments may be based upon the equations provided above. In addition, any practicable means and/or forms of adjustment or transition are contemplated within the scope of the present method and system. Moreover, the predetermined time period for making the adjustments can include 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, etc. and/or any multiple {e.g., integer) of the period between in vivo measurements. Any practicable time periods are contemplated to be within the scope of the present method and system.

[0057] Various other modifications and alterations in the structure and method of operation of the embodiments of the present disclosure will be apparent to those skilled in the art without departing from the scope and spirit of the present disclosure. Although the present disclosure has been described in connection with certain embodiments, it should be understood that the present disclosure as claimed should not be unduly limited to such embodiments. It is intended that the following claims define the scope of the present disclosure and that structures and methods within the scope of these claims and their equivalents be covered thereby.

Claims

What is claimed is:
1. A method implemented using one or more computer processors, comprising:
determining in vivo analyte levels over time based upon analyte data being received from an in vivo analyte sensor;
displaying current analyte levels over time based on the in vivo analyte levels;
determining a reference analyte level based on received reference analyte data from a reference analyte device;
comparing a current in vivo analyte level with the reference analyte level;
displaying the reference analyte level as the current analyte levels until the in vivo analyte level matches the reference analyte level; and
returning to displaying the in vivo analyte levels once the in vivo analyte level matched the reference analyte level.
2. The method of claim 1, wherein comparing the current in vivo analyte level with the reference analyte level includes determining whether a difference between the current in vivo analyte level and the reference analyte level presents a clinical risk.
3. The method of claim 2 further comprising not displaying the reference analyte level as the current analyte levels if the difference between the current in vivo analyte level and the reference analyte level presents the clinical risk.
4. The method of claim 1, wherein displaying the reference analyte level as the current analyte levels includes holding the displayed current analyte level constant over time.
5. The method of claim 1, further comprising determining when the in vivo analyte level matches the reference analyte level.
6. A method implemented using one or more processors, comprising:
determining in vivo analyte levels over time based upon analyte data being received from an in vivo analyte sensor; displaying analyte levels over time based on the in vivo analyte levels; determining a reference analyte level based on received reference analyte data from a reference analyte device;
comparing a current in vivo analyte level with the reference analyte level;
adjusting a next displayed analyte level to the reference analyte level; and
transitioning subsequently displayed analyte levels toward subsequently determined in vivo analyte levels by an incremental amount over a predetermined time period.
7. The method of claim 6, wherein comparing the current in vivo analyte level with the reference analyte level includes determining whether a difference between the current in vivo analyte level and the reference analyte level presents a clinical risk.
8. The method of claim 7 further comprising not adjusting the next or the subsequently displayed analyte levels if the difference between the current in vivo analyte level and the reference analyte level presents the clinical risk.
9. The method of claim 6, wherein transitioning the subsequently displayed analyte levels includes making at least one of a linear transition, an exponential transition, a random transition, a logarithmic transition, a parabolic transition, and a polynomial transition.
10. The method of claim 6, wherein the predetermined time period is an integer multiple of a period between which the analyte levels are displayed.
11. The method of claim 6, wherein adjusting the next displayed analyte level includes adjusting a sensitivity of the in vivo analyte sensor.
12. The method of claim 11, wherein adjusting the sensitivity of the in vivo analyte sensor includes adjusting the sensitivity of the in vivo analyte sensor so that the next displayed analyte level equals the reference analyte level.
13. An apparatus comprising :
a user interface;
one or more processors coupled to the user interface; and
a memory storing instructions which, when executed by the one or more processors, cause the one or more processors to:
determine in vivo analyte levels over time based upon analyte data being received from an in vivo analyte sensor;
display analyte levels over time based on the in vivo analyte levels;
determine a reference analyte level based on received reference analyte data from a reference analyte device;
compare a current in vivo analyte level with the reference analyte level;
adjust a next displayed analyte level to the reference analyte level; and transition subsequently displayed analyte levels toward subsequently determined in vivo analyte levels by an incremental amount over a predetermined time period.
14. The apparatus of claim 13, wherein the instructions to compare the current in vivo analyte level with the reference analyte level include the instructions to determine whether a difference between the current in vivo analyte level and the reference analyte level presents a clinical risk.
15. The apparatus of claim 14 further comprising the instructions not to adjust the next or the subsequently displayed analyte levels if the difference between the current in vivo analyte level and the reference analyte level presents the clinical risk.
16. The apparatus of claim 13, wherein the instructions to transition the subsequently displayed analyte levels include the instructions to make at least one of a linear transition, an exponential transition, a random transition, a logarithmic transition, a parabolic transition, and a polynomial transition to the subsequently displayed analyte levels.
17. The apparatus of claim 13, wherein the predetermined time period is an integer multiple of a period between which the analyte levels are displayed.
18. The apparatus of claim 13, wherein the instructions to adjust the next displayed analyte level include the instructions to adjust a sensitivity of the in vivo analyte sensor.
19. The apparatus of claim 18, wherein the instructions to adjust the sensitivity of the in vivo analyte sensor include the instructions to adjust the sensitivity of the in vivo analyte sensor so that the next displayed analyte level equals the reference analyte level.
20. An integrated analyte monitoring assembly, comprising:
an analyte sensor for transcutaneous positioning through a skin layer and maintained in fluid contact with an interstitial fluid under the skin layer during a predetermined time period, the analyte sensor having a proximal portion and a distal portion; and
sensor electronics coupled to the analyte sensor, the sensor electronics including: a circuit board having a conductive layer and a sensor antenna disposed on the conductive layer;
one or more electrical contacts provided on the circuit board and coupled with the proximal portion of the analyte sensor to maintain continuous electrical communication; and
a data processing component provided on the circuit board and in signal communication with the analyte sensor, the data processing component configured to execute one or more routines for processing signals received from the analyte sensor, the data processing component configured to control the transmission of data associated with the processed signals received from the analyte sensor to a remote location using the sensor antenna in response to a request signal received from the remote location, the data processing component including a memory storing instructions which, when executed by the data processing component, cause the data processing component to:
determine user in vivo analyte levels over time based upon analyte data being received from an in vivo analyte sensor; display analyte levels over time based on the in vivo analyte levels; determine a reference analyte level based on received reference analyte data from a reference analyte device;
compare a current in vivo analyte level with the reference analyte level; adjust a next displayed analyte level to the reference analyte level; and transition subsequently displayed analyte levels toward subsequently determined in vivo analyte levels by an incremental amount over the predetermined time period.
21. The integrated analyte monitoring assembly of claim 20, wherein the instructions to compare the current in vivo analyte level with the reference analyte level include the instructions to determine whether a difference between the current in vivo analyte level and the reference analyte level presents a clinical risk.
22. The integrated analyte monitoring assembly of claim 21 further comprising the instructions not to adjust the next or the subsequently displayed analyte levels if the difference between the current in vivo analyte level and the reference analyte level presents the clinical risk.
23. The integrated analyte monitoring assembly of claim 20, wherein the instructions to transition the subsequently displayed analyte levels include the instructions to make at least one of a linear transition, an exponential transition, a random transition, a logarithmic transition, a parabolic transition, and a polynomial transition to the subsequently displayed analyte levels.
24. The integrated analyte monitoring assembly of claim 20, wherein the predetermined time period is an integer multiple of a period between which the analyte levels are displayed.
25. The integrated analyte monitoring assembly of claim 20, wherein the instructions to adjust the next displayed analyte level include the instructions to adjust a sensitivity of the in vivo analyte sensor so that the next displayed analyte level equals the reference analyte level.
PCT/US2013/057140 2012-08-30 2013-08-28 Modifying a sensitivity value to adjust for lag between in vivo sensor analyte values and an in vitro reference analyte value WO2014036175A1 (en)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
US20100160761A1 (en) * 1998-04-30 2010-06-24 Abbott Diabetes Care Inc. Analyte Monitoring Device and Methods of Use
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