Closed loop blood glucose control algorithm analysis

[0001] The present application claims priority under 35 U.S.C. §119(e) to U.S. provisional application No. 61/173,598 filed Apr. 28, 2009, entitled “Closed Loop Blood Glucose Control Algorithm Analysis”, the disclosure of which is incorporated in its entirety by reference for all purposes.

[0002] A desirable diabetes management and treatment includes a combined continuous blood glucose monitoring and insulin delivery system that operate autonomously. In such systems, control software would monitor the output of the continuous blood glucose monitor and calculate appropriate delivery instructions for the insulin delivery system. Such a system is often referred to as closed loop blood glucose control and the control software is often referred to as a closed loop blood glucose control algorithm.

[0003] The development of a closed loop blood glucose control algorithm is the most challenging aspect of the development of a closed loop blood glucose control system. This challenge arises from complicated features of diabetes management such as noise and delays that are inherent features of blood glucose monitoring and insulin delivery. Another complicating aspect of developing a closed loop blood glucose control algorithm is that individuals can differ significantly in the details of their lifestyle (e.g., diet, activity level) and in the details of their physiology (e.g., size, fitness, insulin sensitivity).

[0004] Furthermore, failure of a closed loop blood glucose control algorithm could potentially have lethal consequences. Thus a closed loop blood glucose control algorithm will need to be comprehensively tested and likely need to be tuned or personalized to each individual user.

[0005] Currently, testing a closed loop blood glucose control algorithm requires the use of a living diabetic subject or a mathematical model of a diabetic subject. The living subject can be animal or human. Testing a closed loop blood glucose control algorithm on a living subject suffers from the disadvantage that such testing is expensive, time consuming and poses significant risks to the health of the test subject. Testing a closed loop blood glucose control algorithm with a mathematical model of a diabetic subject suffers from the fact that human physiology is far too complex to be sufficiently represented by any currently available mathematical model. The main advantage of the method described herein is that it is fast, inexpensive and incurs no risk and also captures the inherent complexity of a live diabetic subject.

[0006] Embodiments of the subject disclosure include device and methods comprising receiving glucose data for a predetermined time period, determining a variation in the glucose level based on the received glucose data, filtering a received glucose data based on the determined variation, substituting a negative change in the glucose data value with a predetermined value to generate a sequence of modified glucose values, and integrating the sequence of modified glucose values to determine an uncontrolled blood glucose excursion condition.

[0007] An apparatus in a further aspect includes a user interface, one or more processors operatively coupled to the data user interface, and a memory for storing instructions which, when executed by the one or more processors, causes the one or more processors to receive glucose data for a predetermined time period, determine a variation in the glucose level based on the received glucose data, filter a received glucose data based on the determined variation, substitute a negative change in the glucose data value with a predetermined value to generate a sequence of modified glucose values, and integrating the sequence of modified glucose values to determine an uncontrolled blood glucose excursion condition.

[0008] In still another aspect, one or more storage devices having processor readable code embodied thereon, the processor readable code for programming one or more processors to perform a control test algorithm comprising receiving glucose data for a predetermined time period, determining a variation in the glucose level based on the received glucose data, filtering a received glucose data based on the determined variation, substituting a negative change in the glucose data value with a predetermined value to generate a sequence of modified glucose values, and integrating the sequence of modified glucose values to determine an uncontrolled blood glucose excursion condition.

[0009] Also provided are systems, computer program products, and kits.

[0010] The following patents, applications and/or publications are incorporated herein by reference for all purposes: U.S. Pat. Nos. 4,545,382; 4,711,245; 5,262,035; 5,262,305; 5,264,104; 5,320,715; 5,509,410; 5,543,326; 5,593,852; 5,601,435; 5,628,890; 5,820,551; 5,822,715; 5,899,855; 5,918,603; 6,071,391; 6,103,033; 6,120,676; 6,121,009; 6,134,461; 6,143,164; 6,144,837; 6,161,095; 6,175,752; 6,270,455; 6,284,478; 6,299,757; 6,338,790; 6,377,894; 6,461,496; 6,503,381; 6,514,460; 6,514,718; 6,540,891; 6,560,471; 6,579,690; 6,591,125; 6,592,745; 6,600,997; 6,605,200; 6,605,201; 6,616,819; 6,618,934; 6,650,471; 6,654,625; 6,676,816; 6,730,200; 6,736,957; 6,746,582; 6,749,740; 6,764,581; 6,773,671; 6,881,551; 6,893,545; 6,932,892; 6,932,894; 6,942,518; 7,167,818; and 7,299,082; U.S. Published Application Nos. 2004/0186365; 2005/0182306; 2007/0056858; 2007/0068807; 2007/0227911; 2007/0233013; 2008/0081977; 2008/0161666; and 2009/0054748; U.S. patent application Ser. Nos. 11/831,866; 11/831,881; 11/831,895; 12/102,839; 12/102,844; 12/102,847; 12/102,855; 12/102,856; 12/152,636; 12/152,648; 12/152,650; 12/152,652; 12/152,657; 12/152,662; 12/152,670; 12/152,673; 12/363,712; 12/131,012; 12/242,823; 12/363,712; 12/393,921; 12/495,709; 12/698,124; 12/699,653; 12/699,844; 12/714,439; 12/761,372; and 12/761,387 and U.S. Provisional Application Ser. Nos. 61/230,686 and 61/227,967.

[0017] Before the present disclosure is described in additional detail, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0018] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. That the upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0019] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[0020] It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.

[0021] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0022] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0023] The figures shown herein are not necessarily drawn to scale, with some components and features being exaggerated for clarity.

[0024] Generally, embodiments of the present disclosure are directed to developing and testing a closed loop blood glucose control algorithm. The embodiments disclosed herein use continuous blood glucose data to construct a realistic test input that may be used as an aid in developing, testing or tuning a closed loop blood glucose control algorithm. In one aspect, the algorithm analyzes a set of continuous blood glucose data and processes it to generate a hypothetical uncontrolled blood glucose excursion. This uncontrolled blood glucose excursion can then be used as a test input to aid in developing, testing or tuning a closed loop blood glucose control algorithm. In one aspect, the approach described in accordance with the various embodiments allows a closed loop blood glucose control algorithm to be custom tailored to the unique requirements of a diabetic individual.

[0025] In one aspect, analysis may be performed on continuously monitored glucose data to generate a tool that may be used to develop, test or tune a closed loop blood glucose control algorithm. A set of continuous blood glucose data shows the increases and decreases in blood glucose corresponding to various metabolic processes that add glucose to or remove glucose from the body. For a diabetic person with poor blood glucose control, these increases and decreases in blood glucose can be very distinct because consumption of carbohydrates and injection of insulin are not well matched.

[0026] FIG. 1 shows a plot of glucose data generated using a continuous glucose monitoring system such as, for example, Freestyle Navigator® Continuous Glucose Monitoring System available from Abbott Diabetes Care Inc., Alameda Calif. It can be seen that the continuous glucose data shown FIG. 1 includes data from a diabetic subject with poor glucose control over a 24 hour period with data points obtained every one minute. As can be further seen from FIG. 1, the overall data set is composed of distinct subsets of data in which blood glucose is continuously increasing (upslopes shown in FIG. 1) and distinct subsets of data in which blood glucose is continuously decreasing (downslopes shown in FIG. 1).

[0027] Additional detailed descriptions of embodiments of the analyte monitoring system, embodiments of its various components are provided in U.S. Pat. Nos. 5,262,035; 5,264,104; 5,262,305; 5,320,715; 5,593,852; 6,103,033; 6,134,461; 6,175,752; 6,560,471; 6,579,690; 6,605,200; 6,654,625; 6,746,582; and 6,932,894; and in U.S. Published Patent Application No. 2004/0186365, the disclosures of which are herein incorporated by reference. Furthermore, detailed description of signal processing related to sensor initialization, signal filtering, and processing in analyte monitoring systems can be found in U.S. Pat. Nos. 6,175,751, 6,560,471, and in U.S. patent application Ser. No. 12/152,649 filed May 14, 2008, disclosure of each of which are incorporated herein by reference for all purposes. Additionally, details of closed loop control system with safety parameters are described in U.S. Published Patent Application No. US2009/0105636 filed Aug. 31, 2008, the disclosure of which is incorporated herein by reference for all purposes.

[0028] As discussed above, this pattern or distinct subset may be an indication that for the individual from whom the data set was derived, consumption of carbohydrates and injection of insulin are not well matched. Accordingly, in one aspect of the present disclosure, the subsets of data in which blood glucose is continuously increasing may be separated from the subsets of data in which blood glucose is continuously decreasing. The subsets of data in which blood glucose is decreasing are then removed and replaced with an artificially constructed subset of blood glucose data that serves as an extrapolation of the subset of increasing blood glucose data that preceded it. In one aspect, the subsets of data in which blood glucose is continuously increasing and the artificially constructed subset of blood glucose data may be associated or linked together. This results in a plot of how blood glucose level increases with time if glucose was never consumed i.e., a hypothetical uncontrolled blood glucose excursion. This hypothetical uncontrolled blood glucose excursion may then be used as a test input to a closed loop blood glucose control algorithm to aid in developing, testing or tuning that algorithm. This analysis of the blood glucose data can readily be performed using a conventional software program such as a spreadsheet program.

[0029] In one aspect of the present disclosure, continuously monitored glucose data such as that shown in FIG. 1 is collected. As the collected data indicates, for example, shown in FIG. 1, the increase and decrease of blood glucose value over time may be due to various metabolic processes including the influx of glucose from the gut, release and uptake of glucose from the liver and insulin dependent utilization of glucose by cells in the body. The collected data may be uploaded into a spreadsheet program for processing as a time sequential data. For reference, the time stamp for each data point is associated with each one minute data. The resulting data is then plotted as, for example, shown in FIG. 1.

[0030] Using the collected and/or plotted data set, the change in glucose value from one minute to the next is determined. For example, the change in blood glucose value from one minute to the next can be determined. In one aspect, minute to minute variation in blood glucose level that are unrealistically large may also be filtered out as they are likely due to noise or signal artifacts in the continuous glucose sensor. For example, it can be seen that a rate of change in blood glucose level greater than 2.5 mg/dl per minute is likely to be caused by noise in the continuous blood glucose monitoring system. FIG. 2 illustrates a plot of the filtered minute to minute changes in blood glucose data based on the data of FIG. 1.

[0031] As a separate set of data, in one aspect, negatively valued changes in blood glucose are filtered out and replaced. In one aspect, different approaches or values may be used for replacement values to separate the subsets of blood glucose data where blood glucose is increasing from those subsets of data where blood glucose is decreasing. The subsets of blood glucose data where blood glucose is increasing are then linked or associated with an artificially constructed subset of blood glucose data. The artificially constructed subset of blood glucose data is generated so as to effect an extrapolation of the previous subset of blood glucose data where blood glucose is increasing.

[0032] Specifically, in one embodiment, negatively valued changes in blood glucose may be replaced with a zero value. In this manner, the artificially constructed subset of blood glucose data has the effect of holding the blood glucose constant between the subsets of increasing blood glucose. An example of how this would be implemented as a logic statement is shown in equation 1 below where “n” is the specific blood glucose value in question.
if n<0, then n=0, otherwise n=n  (1)

[0033] In an alternative embodiment negatively valued changes in blood glucose are replaced with a constant positive value. In this manner, the artificially constructed subset of blood glucose data may be generated so as to affect a constant increase in blood glucose value. An example of how this would be implemented as a logic statement is shown in equation 2 below where “n” is to the specific blood glucose value in question and “x” is the constant rate of blood glucose increase in the artificially constructed subset of blood glucose data.
if n<0, then n=x, otherwise n=n  (2)

[0034] In yet a further embodiment, negatively valued changes in blood glucose may be replaced with an average value of all or part of the previous subset of increasing blood glucose value. In this manner, the glucose trend that was present in the previous subset of increasing blood glucose value may be preserved in the artificially constructed subset of blood glucose data. The artificially constructed subset of blood glucose data may extrapolate the trend in blood glucose data that was present in the previous subset of blood glucose data that was increasing. An example of this approach as a logic statement is shown in equation 3 below where “n” is the specific blood glucose value in question and “y” is the number of previous positively valued blood glucose values which are averaged.
if n<0, then n=average previous y positive values, otherwise n=n  (3)

[0035] FIG. 3 illustrates a plot of the aforementioned filtered minute to minute changes in blood glucose data. As can be seen, the subsets of data where blood glucose level is decreasing are removed by replacing negatively valued changes in blood glucose with the average of the previous 10 positively valued changes in blood glucose.

[0036] In still a further embodiment, the negatively valued changes in blood glucose may be replaced with a blood glucose value that is a predefined function of all or part of the previous subset of increasing blood glucose values. For example, a linear regression curve fit may be applied to all or part of the previous subset of increasing blood glucose values. This linear regression curve fit may be used to extrapolate values to replace decreasing blood glucose values. Alternatively, a higher order curve fit may be applied to all or part of the previous subset of increasing blood glucose values. This curve fit can then be used to extrapolate values to replace decreasing blood glucose values.

[0037] After obtaining the filtered analyzed data set as discussed above, the minute to minute positive changes in blood glucose level are integrated into a continuous uncontrolled blood glucose excursion. In one aspect, integrating the minute to minute positive changes in blood glucose level into the continuous uncontrolled blood glucose excursion may be achieved by selecting a blood glucose value to start with, for example, 100 mg/dl, and adding each minute's blood glucose change to this initial value.

[0038] FIG. 4 illustrates a plot of an uncontrolled blood glucose excursion generated from the data in FIG. 3. The plot shown in FIG. 4 includes all of the actual subsets of blood glucose data from FIG. 1 where blood glucose is increasing linked together with artificially constructed subsets of blood glucose data that are extrapolations of the subsets of increasing blood glucose data that preceded them. The uncontrolled blood glucose excursion in FIG. 4 shows a change in blood glucose of about 1400 mg/dl over the course of 24 hrs. For a 70 kg person, this may result from the consumption of about 200 grams (1000 calories) of carbohydrates which is a reasonable amount for a daily consumption. Moreover, as shown in FIG. 4, the subtle features and irregularities of blood glucose data that arise as a result of the unique features of an individual's lifestyle and physiology are illustrated.

[0039] In one aspect, the profile illustrated in FIG. 4 is used as a test input to a closed loop control simulation. FIG. 5 illustrates an example of output from a simple closed loop control simulation. The simulation uses the data in FIG. 4 as a test input and a PID control algorithm. The control simulation additionally uses a model for insulin sensitivity and for insulin pharmacokinetics. Blood glucose is shown on the upper curve and insulin concentration is shown on the lower curve.

[0040] The insulin concentration is due to insulin that was administered by the controller in response to the blood glucose behavior in FIG. 4. The various values for controller gain can readily be changed to affect optimal control. Values for insulin sensitivity and insulin pharmacokinetics as well as parameters for the continuous blood glucose monitor's performance can also be changed to assess the robustness of the controller.

[0041] FIG. 6 is a block diagram illustrating an overall system for executing closed loop control simulation routines in accordance with embodiments of the present disclosure. Referring to FIG. 6, in certain embodiments, data, such as glucose data, for use in the closed loop control simulation routines described above, is received at a system 600 via a communication module 603. The communication module 603 may be a wired connection port configured to receive data via a wired connection, such as, among others, a universal serial bus (USB) connection, RS-232 serial connection, parallel connection, or Ethernet connection, or may be a wireless communication module configured for, among others, radio frequency (RF) communication protocol, Bluetooth® communication protocol, infrared (IR) communication protocol, or 802.11 WiFi communication protocol. The communication module 603 is coupled to a processor 601 or other processing unit. The processor 601, may be, among others, a microprocessor, microcontroller, CPU, or an application specific integrated circuit (ASIC). The processor 601 and the communication module 603 are also coupled to a memory 602. In certain embodiments, the memory 602 may be integral with the processor 601. In other embodiments, the memory 602 may be a separate unit external from the processor 601 unit and coupled via a communication interface.

[0042] Still referring to FIG. 6, the glucose data received at the communication module 603 is stored in the memory 602 under control of the processor 601. The memory 602 additionally stores programming instructions for execution by the processor 601 for executing closed loop control simulation routines, such as the closed loop control simulation routines described above, based on the glucose data received at the communication module 603 and stored in the memory 602. The system may further include an output module 604 configured for transmission or output of the results of the closed loop control simulation routines. In certain embodiments the output module 604 transmits the results of the closed loop control simulation routines to an external display device for display to a patient or user. In other embodiments the output module 604 of the system 600 is a display or other output device for displaying or otherwise outputting (for example via audio output) results of the closed loop control simulation routines to the user.

[0043] In this manner, in aspects of the present disclosure it can be seen that for a diabetic person with poor blood glucose control, a set of continuous blood glucose data collected over a long period of time may include significant subsets of continuous data where the measured change in blood glucose is dominated by the influx of glucose from the gut and where insulin dependent utilization of glucose contributes insignificantly. In these subsets of continuous data, blood glucose level rises at or near its maximum possible rate. Accordingly, in one aspect, the one or more routines described herein links or associates those subsets of continuous data together with artificially constructed subsets of blood glucose data that are extrapolations of the blood glucose data that preceded them. This forms a hypothetical uncontrolled blood glucose excursion which can then be used as a tool in the development, testing and tuning of a closed loop blood glucose control algorithm.

[0044] A method for developing and testing a closed loop blood glucose control algorithms is disclosed. The method uses continuous blood glucose data to develop, test or tune a closed loop blood glucose control algorithm. The process takes a string of continuous blood glucose data and mathematically processes it to produce a hypothetical uncontrolled blood glucose excursion. This uncontrolled blood glucose excursion can then be used as a test input to aid in developing, testing or tuning a closed loop blood glucose control algorithm. This method will allow a closed loop blood glucose control algorithm to be custom tailored to the unique requirements of an individual.

[0045] In the manner described above, in accordance with embodiments of the present disclosure, method for developing and testing a closed loop blood glucose control algorithm is provided. In one aspect, continuous blood glucose data may be used to generate a test input that can be used as an aid in developing, testing or tuning a closed loop blood glucose control algorithm. The routine may include a set of continuous blood glucose data which is analyzed to generate or determine a hypothetical uncontrolled blood glucose excursion. The uncontrolled blood glucose excursion may be used as a test input to aid in developing, testing or tuning a closed loop blood glucose control algorithm. In one aspect, this approach may allow a closed loop blood glucose control algorithm to be custom tailored to the unique requirements of a diabetic individual.

[0046] In one embodiment, a method may include receiving glucose data for a predetermined time period, determining a variation in the glucose level based on the received glucose data, filtering the received glucose data based on the determined variation, substituting a negative change in the glucose data value with a predetermined value to generate a sequence of modified glucose values, and integrating the sequence of modified glucose values to determine an uncontrolled blood glucose excursion condition.

[0047] In one aspect, the predetermined value may include an average value, where the average value may include an average of ten prior values. Alternatively, or in addition to, the average value may include a weighted average value, which may be an equally or unequally weighted average value.

[0048] In a further aspect, filtering based on the predetermined variation may include filtering out glucose values associated with a negative change, where the negative change may be determined based on an immediate prior glucose value.

[0049] In another embodiment, an apparatus is disclosed which may include a user interface, one or more processors operatively coupled to the user interface, and a memory for storing instructions which, when executed by the one or more processors, causes the one or more processors to receive glucose data for a predetermined time period, determine a variation in the glucose level based on the received glucose data, filter the received glucose data based on the determined variation, substitute a negative change in the glucose data value with a predetermined value to generate a sequence of modified glucose values, and integrating the sequence of modified glucose values to determine an uncontrolled blood glucose excursion condition.

[0050] In another aspect, the memory for storing instructions which, when executed by the one or more processors, may cause the one or more processors to filter out glucose values associated with a negative change, where the negative change may be determined based on an immediate prior glucose value.

[0051] In still another aspect, one or more storage devices having processor readable code embodied thereon, said processor readable code for programming one or more processors to perform a control test algorithm may comprise receiving glucose data for a predetermined time period, determining a variation in the glucose level based on the received glucose data, filtering the received glucose data based on the determined variation, substituting a negative change in the glucose data value with a predetermined value to generate a sequence of modified glucose values, and integrating the sequence of modified glucose values to determine an uncontrolled blood glucose excursion condition.

[0052] Various other modifications and alterations in the structure and method of operation of this disclosure will be apparent to those skilled in the art without departing from the scope and spirit of the embodiments of the present disclosure. Although the present disclosure has been described in connection with particular embodiments, it should be understood that the present disclosure as claimed should not be unduly limited to such particular 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.