Patent Description:
The present technology is generally related to sensor technology, including sensors used for sensing a variety of physiological parameters, e.g., glucose concentration.

Over the years, a variety of sensors have been developed for detecting and/or quantifying specific agents or compositions in a patient's blood, which enable patients and medical personnel to monitor physiological conditions within the patient's body. Illustratively, subjects may wish to monitor blood glucose levels in a subject's body on a continuing basis. Thus, glucose sensors have been developed for use in obtaining an indication of blood glucose levels in a diabetic patient. Such readings are useful in monitoring and/or adjusting a treatment regimen which typically includes the regular administration of insulin to the patient. Presently, a patient can measure his/her blood glucose ("BG") using a BG measurement device (i.e., glucose meter), such as a test strip meter, a continuous glucose measurement system (or a continuous glucose monitor), or a hospital BG test. BG measurement devices use various methods to measure the BG level of a patient, such as a sample of the patient's blood, a sensor in contact with a bodily fluid, an optical sensor, an enzymatic sensor, or a fluorescent sensor. When the BG measurement device has generated a BG measurement, the measurement is displayed on the BG measurement device.

<CIT> relates to methods, systems, and devices for continuous glucose monitoring. <CIT> describes a continuous glucose monitoring system that may utilize electrode current signals, Electrochemical Impedance Spectroscopy (EIS), and Vcntr values to optimize sensor glucose calculation in such a way as to enable reduction of the need for blood glucose calibration requests from users. A vector of parameters estimated from EIS measurements and from non-EIS related metrics is used to train artificial neural networks (ANN), support vector machines (SVM), or genetic algorithms to detect sensitivity loss.

The relationship between glucose sensitivity and sensor features (e.g., sensor electrical properties) of sensor devices is essential to accurate modeling, as it affects whether a current continuous glucose monitoring ("CGM") system utilizes measurements from a sensor device or blank the sensor device (e.g., remove, ignore, or forego to transmit the sensor data to the sensor device or any other device with a display interface). However, a single model is often unable to accurately depict this complex relationship. For example, sensor electrical properties such as time, wear, battery, calibration, and other properties can affect glucose sensitivity in complex ways that are difficult to capture with a single model. Additionally, glucose sensitivity may vary as sensor features change, for example, due to variability in the sensing environment, physiological dynamics, or sensor manufacturing. Methods and systems described herein partition an input signal feature space into a plurality of contiguous subspaces. The system selects and trains a model for each subspace from a plurality of types of models. Such input signal feature space partitioning is often unsuccessful in conjunction with current systems. In fact, input signal feature space partitioning often leads to significant decreases in accuracy and performance due to a decrease in data available within each space. However, the methods and systems described herein utilize smart partitioning and training techniques in order to generate an accurate model. The resulting mosaic model is more accurate than a single model for determining the relationship between glucose sensitivity and a sensor electrical property of a sensor device.

The accuracy of this modeling technique improves upon the ability of the CGM system to comply with government standards of sensor devices. Government agencies (e.g., the Federal Drug Administration ("FDA")) impose restrictions and requirements for the sensitivity and accuracy of CGMs. For example, CGM devices are required to meet numerous criteria (e.g., FDA's integrated continuous glucose monitoring ("iCGM") criteria) in order for the sensor data to be considered accurate. In order to comply with the iCGM criteria, the CGM system must accurately model the relationship between glucose sensitivity and sensor electrical properties of a sensor device. The system may use the output of the mosaic of models to determine if the sensor device meets the iCGM standards. If the system determines that the sensor device is compliant with the iCGM criteria, the system may utilize readings from the sensor device. If the system determines that the sensor device is not compliant with the iCGM criteria, the system may blank the sensor data from a user device (e.g., remove, ignore, or forego to transmit the sensor data to the sensor device or any other device with a display interface). Thus, the methods, systems, and devices described herein allow for improved CGM techniques that are compatible with the FDA's iCGM criteria.

More particularly, the methods, systems, and devices describe partitioning an input signal feature space into a plurality of contiguous subspaces. For example, the input signal feature space may relate glucose sensitivity and a sensor electrical property (e.g., wear, time, battery life, calibration, etc.) associated with a sensor device. The system may train a machine learning model for each subspace to determine glucose sensitivity based on a range of values associated with the sensor electrical property for the subspace. In some embodiments, the machine learning model may take as inputs sensor data from the sensor device and may use training data as feedback. The training data may include clinical data on glucose sensitivity. In some embodiments, the system may also receive sensor data (e.g., relating to wear time, battery life, calibration, electrical data, or other sensor properties) associated with the sensor device from the sensor device. The system may input the sensor data into the machine learning model and may receive an output from the machine learning model indicating glucose sensitivity.

With input signal feature space division, discrepancies may arise at the boundaries between subspaces. For example, the separate models of adjacent subspaces may not align precisely, leading to gaps in the mosaic model. Therefore, methods and systems described herein detail smoothing and blending methods for correcting discrepancies between models. For example, the system may extend the model for each subspace into the adjacent subspaces. Therefore, the area surrounding the boundaries of the subspaces may comprise several overlapping models. In some embodiments, the system may build a composite model based on the models of the entire input signal feature space. The system may overlay the composite model on top of the models of each subspace (e.g., overlaying the entire input signal feature space) and blend the composite model with the models of each subspace. In some embodiments, the system may use other methods of smoothing or blending the glucose sensitivity outputs at the subspace boundaries in order to generate an accurate and smooth mosaic model.

In some aspects, methods, systems, and devices for continuous glucose monitoring are described. For example, the system may partition an input signal feature space into a plurality of contiguous subspaces, the input signal feature space relating glucose sensitivity and a sensor electrical property associated with a sensor device. In some embodiments, for each subspace, the system may train the machine learning model to predict glucose sensitivity based on a range of values associated with the sensor electrical property for the subspace. In some embodiments, the system may train the machine learning model using training data that includes clinical data on glucose sensitivity. The system may receive sensor data from the sensor device and may input the sensor data into the machine learning model. The system may receive an output from the machine learning model indicating glucose sensitivity. In some embodiments, the system may determine whether to blank the sensor device (e.g., remove, ignore, or forego to transmit the sensor data to the sensor device or any other device with a display interface) based on the output from the machine learning model.

Various other aspects, features, and advantages will be apparent through the detailed description and the drawings attached hereto. It is also to be understood that both the foregoing general description and the following detailed description are examples and not restrictive of the scope of the invention The invention is defined in claims <NUM>, <NUM> and <NUM>. As used in the specification and in the claims, the singular forms of "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In addition, as used in the specification and the claims, the term "or" means "and/or" unless the context clearly dictates otherwise. Additionally, as used in the specification "a portion," refers to a sub-part of, or the entirety of, a given item (e.g., data) unless the context clearly dictates otherwise.

A detailed description of embodiments of the invention will be made with reference to the accompanying drawings, wherein like numerals designate corresponding parts in the figures.

In the following description, reference is made to the accompanying drawings which form a part hereof and which illustrate several embodiments of the present inventions. It is understood that other embodiments may be utilized, and structural and operational changes may be made without departing from the scope of the present inventions.

The inventions herein are described below with reference to flowchart illustrations of methods, systems, devices, apparatus, and programming and computer program products. It will be understood that each block of the flowchart illustrations, and combinations of blocks in the flowchart illustrations, can be implemented by programing instructions, including computer program instructions (as can any menu screens described in the figures). These computer program instructions may be loaded onto a computer or other programmable data processing apparatus (such as a controller, microcontroller, or processor in a sensor electronics device) to produce a machine, such that the instructions which execute on the computer or other programmable data processing apparatus create instructions for implementing the functions specified in the flowchart block or blocks. These computer program instructions may also be stored in a computer-readable memory that can direct a computer or other programmable data processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable memory produce an article of manufacture including instructions which implement the function specified in the flowchart block or blocks. The computer program instructions may also be loaded onto a computer or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide steps for implementing the functions specified in the flowchart block or blocks, and/or menus presented herein. Programming instructions may also be stored in and/or implemented via electronic circuitry (e.g., storage circuitry, processing circuitry), including integrated circuits (ICs) and Application Specific Integrated Circuits (ASICs) used in conjunction with sensor devices, apparatuses, and systems. The following terms and definitions may also be used herein:.

<FIG> illustrates wearable sensor electronics devices <NUM> and <NUM>, in accordance with one or more embodiments. In some embodiments, wearable sensor electronics device <NUM> may be an infusion pump. In some embodiments, the infusion pump may include a display. In some embodiments, wearable sensor electronics device <NUM> may be a combination infusion pump/glucose sensor. In some embodiments, wearable sensor electronics device <NUM> may be a cellular phone or any computing device. In some embodiments, wearable sensor electronics devices <NUM> and <NUM> may include a computer, a personal digital assistant, a pager, or any other suitable wearable device. In some embodiments, wearable sensor electronics devices <NUM> and <NUM> may house components described below in relation to <FIG>.

<FIG> is a perspective view of a subcutaneous sensor insertion set and a block diagram of a sensor electronics device (e.g., wearable sensor electronics devices <NUM> or <NUM>, as shown in <FIG>, or any other suitable sensor electronics device). As illustrated in <FIG>, a subcutaneous sensor set <NUM> is provided for subcutaneous placement of an active portion of a flexible sensor <NUM> (see, e.g., <FIG>), or the like, at a selected site in the body of a user. The subcutaneous or percutaneous portion of the sensor set <NUM> includes a hollow, slotted insertion needle <NUM>, and a cannula <NUM>. The needle <NUM> is used to facilitate quick and easy subcutaneous placement of the cannula <NUM> at the subcutaneous insertion site. Inside the cannula <NUM> is a sensing portion <NUM> of the sensor <NUM> to expose one or more sensor electrodes <NUM> to the user's bodily fluids through a window <NUM> formed in the cannula <NUM>. In one embodiment, the one or more sensor electrodes <NUM> may include a counter electrode, a reference electrode, and one or more working electrodes. After insertion, the insertion needle <NUM> is withdrawn to leave the cannula <NUM> with the sensing portion <NUM> and the sensor electrodes <NUM> in place at the selected insertion site.

In particular embodiments, the subcutaneous sensor set <NUM> facilitates accurate placement of a flexible thin film electrochemical sensor <NUM> of the type used for monitoring specific blood parameters representative of a user's condition. The sensor <NUM> monitors glucose levels in the body and may be used in conjunction with automated or semi-automated medication infusion pumps (e.g., wearable sensor electronics device <NUM>, as shown in <FIG>) of the external or implantable type to control delivery of insulin to a diabetic patient, as described, e.g., in <CIT>; <CIT>; <CIT>or<CIT>,.

Particular embodiments of the flexible electrochemical sensor <NUM> are constructed in accordance with thin film mask techniques to include elongated thin film conductors embedded or encased between layers of a selected insulative material such as polyimide film or sheet, and membranes. The sensor electrodes <NUM> at a tip end of the sensing portion <NUM> are exposed through one of the insulative layers for direct contact with patient blood or other body fluids, when the sensing portion <NUM> (or active portion) of the sensor <NUM> is subcutaneously placed at an insertion site. The sensing portion <NUM> is joined to a connection portion <NUM> that terminates in conductive contact pads, or the like, which are also exposed through one of the insulative layers. In alternative embodiments, other types of implantable sensors, such as chemical based, optical based, or the like, may be used.

As is known in the art, the connection portion <NUM> and the contact pads are generally adapted for a direct wired electrical connection to a suitable monitor or sensor electronics device <NUM> (e.g., wearable sensor electronics devices <NUM> or <NUM>, as shown in <FIG>, or any other suitable sensor electronics device) for monitoring a user's condition in response to signals derived from the sensor electrodes <NUM>. Further description of flexible thin film sensors of this general type are to be found in <CIT>, entitled METHOD OF FABRICATING THIN FILM SENSORS, The connection portion <NUM> may be conveniently connected electrically to the monitor or sensor electronics device <NUM> or by a connector block <NUM> (or the like) as shown and described in <CIT>, entitled FLEX CIRCUIT CONNECTOR. Thus, in accordance with some embodiments, subcutaneous sensor sets <NUM> may be configured or formed to work with either a wired or a wireless characteristic monitor system.

The sensor electrodes <NUM> may be used in a variety of sensing applications and may be configured in a variety of ways. For example, the sensor electrodes <NUM> may be used in physiological parameter sensing applications in which some type of biomolecule is used as a catalytic agent. For example, the sensor electrodes <NUM> may be used in a glucose and oxygen sensor having a glucose oxidase (GOx) enzyme catalyzing a reaction with the sensor electrodes <NUM>. The sensor electrodes <NUM>, along with a biomolecule or some other catalytic agent, may be placed in a human body in a vascular or non-vascular environment. For example, the sensor electrodes <NUM> and biomolecule may be placed in a vein and be subjected to a blood stream or may be placed in a subcutaneous or peritoneal region of the human body.

The monitor <NUM> may also be referred to as a sensor electronics device <NUM>. The monitor <NUM> may include a power source <NUM>, a sensor interface <NUM>, processing electronics <NUM>, and data formatting electronics <NUM>. The monitor <NUM> may be coupled to the sensor set <NUM> by a cable <NUM> through a connector that is electrically coupled to the connector block <NUM> of the connection portion <NUM>. In an alternative embodiment, the cable may be omitted. In this embodiment, the monitor <NUM> may include an appropriate connector for direct connection to the connection portion <NUM> of the sensor set <NUM>. The sensor set <NUM> may be modified to have the connector portion <NUM> positioned at a different location, e.g., on top of the sensor set to facilitate placement of the monitor <NUM> over the sensor set.

In one embodiment, the sensor interface <NUM>, the processing electronics <NUM>, and the data formatting electronics <NUM> are formed as separate semiconductor chips, however, alternative embodiments may combine the various semiconductor chips into a single, or multiple customized semiconductor chips. The sensor interface <NUM> connects with the cable <NUM> that is connected with the sensor set <NUM>.

The power source <NUM> may be a battery. The battery can include three series silver oxide <NUM> battery cells. In alternative embodiments, different battery chemistries may be utilized, such as lithium-based chemistries, alkaline batteries, nickel metal hydride, or the like, and a different number of batteries may be used. The monitor <NUM> provides power to the sensor set via the power source <NUM>, through the cable <NUM> and cable connector <NUM>. In one embodiment, the power is a voltage provided to the sensor set <NUM>. In another embodiment, the power is a current provided to the sensor set <NUM>. In an embodiment, the power is a voltage provided at a specific voltage to the sensor set <NUM>.

<FIG> illustrates an implantable sensor, and electronics for driving the implantable sensor in accordance with one embodiment. <FIG> shows a substrate <NUM> having two sides, a first side <NUM> of which contains an electrode configuration and a second side <NUM> of which contains electronic circuitry (e.g., storage circuitry, processing circuitry, etc.). As may be seen in <FIG>, a first side <NUM> of the substrate comprises two counter electrode-working electrode pairs <NUM>, <NUM>, <NUM>, <NUM> on opposite sides of a reference electrode <NUM>. A second side <NUM> of the substrate comprises electronic circuitry. As shown, the electronic circuitry may be enclosed in a hermetically sealed casing <NUM>, providing a protective housing for the electronic circuitry. This allows the sensor substrate <NUM> to be inserted into a vascular environment or other environment which may subject the electronic circuitry to fluids. By sealing the electronic circuitry in a hermetically sealed casing <NUM>, the electronic circuitry may operate without risk of short circuiting by the surrounding fluids. Also shown in <FIG> are pads <NUM> to which the input and output lines of the electronic circuitry may be connected. The electronic circuitry itself may be fabricated in a variety of ways. According to an embodiment, the electronic circuitry may be fabricated as an integrated circuit using techniques common in the industry.

<FIG> illustrates a general block diagram of an electronic circuit for sensing an output of a sensor according to one embodiment. At least one pair of sensor electrodes <NUM> may interface to a data converter <NUM>, the output of which may interface to a counter <NUM>. The counter <NUM> may be controlled by control logic <NUM>. The output of the counter <NUM> may connect to a line interface <NUM>. The line interface <NUM> may be connected to input and output lines <NUM> and may also connect to the control logic <NUM>. The input and output lines <NUM> may also be connected to a power rectifier <NUM>.

The sensor electrodes <NUM> may be used in a variety of sensing applications and may be configured in a variety of ways. For example, the sensor electrodes <NUM> may be used in physiological parameter sensing applications in which some type of biomolecule is used as a catalytic agent. For example, the sensor electrodes <NUM> may be used in a glucose and oxygen sensor having a GOx enzyme catalyzing a reaction with the sensor electrodes <NUM>. The sensor electrodes <NUM>, along with a biomolecule or some other catalytic agent, may be placed in a human body in a vascular or non-vascular environment. For example, the sensor electrodes <NUM> and biomolecule may be placed in a vein and be subjected to a blood stream.

<FIG> illustrates a block diagram of a sensor electronics device (e.g., wearable sensor electronics devices <NUM> or <NUM>, as shown in <FIG>, or any other suitable sensor electronics device) and a sensor including a plurality of electrodes according to an embodiment herein. <FIG> includes system <NUM>. System <NUM> includes a sensor <NUM> and a sensor electronics device <NUM>. The sensor <NUM> includes a counter electrode <NUM>, a reference electrode <NUM>, and a working electrode <NUM>. The sensor electronics device <NUM> includes a power supply <NUM>, a regulator <NUM>, a signal processor <NUM>, a measurement processor <NUM>, and a display/transmission module <NUM>. The power supply <NUM> provides power (in the form of either a voltage, a current, or a voltage including a current) to the regulator <NUM>. The regulator <NUM> transmits a regulated voltage to the sensor <NUM>. In one embodiment, the regulator <NUM> transmits a voltage to the counter electrode <NUM> of the sensor <NUM>.

The sensor <NUM> creates a sensor signal indicative of a concentration of a physiological characteristic being measured. For example, the sensor signal may be indicative of a blood glucose reading. In an embodiment utilizing subcutaneous sensors, the sensor signal may represent a level of hydrogen peroxide in a subject. In an embodiment where blood or cranial sensors are utilized, the amount of oxygen is being measured by the sensor and is represented by the sensor signal. In an embodiment utilizing implantable or long-term sensors, the sensor signal may represent a level of oxygen in the subject. The sensor signal is measured at the working electrode <NUM>. In one embodiment, the sensor signal may be a current measured at the working electrode. In an embodiment, the sensor signal may be a voltage measured at the working electrode.

The signal processor <NUM> receives the sensor signal (e.g., a measured current or voltage) after the sensor signal is measured at the sensor <NUM> (e.g., the working electrode). The signal processor <NUM> processes the sensor signal and generates a processed sensor signal. The measurement processor <NUM> receives the processed sensor signal and calibrates the processed sensor signal utilizing reference values. In one embodiment, the reference values are stored in a reference memory and provided to the measurement processor <NUM>. The measurement processor <NUM> generates sensor measurements. The sensor measurements may be stored in a measurement memory (not shown) or by circuitry (e.g., storage circuitry). The sensor measurements may be sent to a display/transmission device to be either displayed on a display in a housing with the sensor electronics or transmitted to an external device.

The sensor electronics device <NUM> may be a monitor which includes a display to display physiological characteristics readings. The sensor electronics device <NUM> may also be installed in a desktop computer, a pager, a television including communications capabilities, a laptop computer, a server, a network computer, a personal digital assistant (PDA), a portable telephone including computer functions, an infusion pump including a display (e.g., wearable sensor electronics device <NUM>, as shown in <FIG>), a glucose sensor including a display, and/or a combination infusion pump/glucose sensor (e.g., wearable sensor electronics device <NUM>, as shown in <FIG>). The sensor electronics device <NUM> may be housed in a blackberry (e.g., wearable sensor electronics device <NUM>, as shown in <FIG>), a network device, a home network device, or an appliance connected to a home network.

<FIG> also includes system <NUM>. System <NUM> includes a sensor electronics device <NUM> and a sensor <NUM>. The sensor includes a counter electrode <NUM>, a reference electrode <NUM>, and a working electrode <NUM>. The sensor electronics device <NUM> includes a microcontroller <NUM> and a digital-to-analog converter (DAC) <NUM>. The sensor electronics device <NUM> may also include a current-to-frequency converter (I/F converter) <NUM>.

The microcontroller <NUM> includes software program code, which when executed, or programmable logic which, causes the microcontroller <NUM> to transmit a signal to the DAC <NUM>, where the signal is representative of a voltage level or value that is to be applied to the sensor <NUM>. The DAC <NUM> receives the signal and generates the voltage value at the level instructed by the microcontroller <NUM>. In one embodiment, the microcontroller <NUM> may change the representation of the voltage level in the signal frequently or infrequently. Illustratively, the signal from the microcontroller <NUM> may instruct the DAC <NUM> to apply a first voltage value for one second and a second voltage value for two seconds.

The sensor <NUM> may receive the voltage level or value. In one embodiment, the counter electrode <NUM> may receive the output of an operational amplifier which has as inputs the reference voltage and the voltage value from the DAC <NUM>. The application of the voltage level causes the sensor <NUM> to create a sensor signal indicative of a concentration of a physiological characteristic being measured. In an embodiment, the microcontroller <NUM> may measure the sensor signal (e.g., a current value) from the working electrode. Illustratively, a sensor signal measurement circuit <NUM> may measure the sensor signal. In an embodiment, the sensor signal measurement circuit <NUM> may include a resistor and the current may be passed through the resistor to measure the value of the sensor signal. In an embodiment, the sensor signal may be a current level signal and the sensor signal measurement circuit <NUM> may be a current-to-frequency (I/F) converter <NUM>. The current-to-frequency converter <NUM> may measure the sensor signal in terms of a current reading, convert it to a frequency-based sensor signal, and transmit the frequency-based sensor signal to the microcontroller <NUM>. In some embodiments, the microcontroller <NUM> may be able to receive frequency-based sensor signals easier than non-frequency-based sensor signals. The microcontroller <NUM> receives the sensor signal, whether frequency-based or non-frequency-based, and determines a value for the physiological characteristic of a subject, such as a blood glucose level. The microcontroller <NUM> may include program code, which when executed or run, is able to receive the sensor signal and convert the sensor signal to a physiological characteristic value. In one embodiment, the microcontroller <NUM> may convert the sensor signal to a blood glucose level. In an embodiment, the microcontroller <NUM> may utilize measurements stored within an internal memory or by circuitry (e.g., storage circuitry) in order to determine the blood glucose level of the subject. In an embodiment, the microcontroller <NUM> may utilize measurements stored within a memory external to the microcontroller <NUM> or by circuitry to assist in determining the blood glucose level of the subject.

After the physiological characteristic value is determined by the microcontroller <NUM>, the microcontroller <NUM> may store measurements of the physiological characteristic values for a number of time periods. For example, a blood glucose value may be sent to the microcontroller <NUM> from the sensor in intervals (e.g., every second or five seconds), and the microcontroller may save sensor measurements in intervals (e.g., for five minutes or ten minutes of BG readings). The microcontroller <NUM> may transfer the measurements of the physiological characteristic values to a display on the sensor electronics device <NUM>. For example, the sensor electronics device <NUM> may be a monitor which includes a display that provides a blood glucose reading for a subject. In one embodiment, the microcontroller <NUM> may transfer the measurements of the physiological characteristic values to an output interface of the microcontroller <NUM>. The output interface of the microcontroller <NUM> may transfer the measurements of the physiological characteristic values, e.g., blood glucose values, to an external device, e.g., an infusion pump (e.g., wearable sensor electronics device <NUM>, as shown in <FIG>), a combined infusion pump/glucose meter (e.g., wearable sensor electronics device <NUM>, as shown in <FIG>), a computer, a personal digital assistant, a pager, a network appliance, a server, a cellular phone (e.g., wearable sensor electronics device <NUM>, as shown in <FIG>), or any computing device.

<FIG> illustrates an electronic block diagram of the sensor electrodes and a voltage being applied to the sensor electrodes according to an embodiment. In some embodiments, <FIG> may illustrate an electrode with a GOx sensor and/or an electrode capable of sensing GOx. For example, <FIG> may illustrate a working electrode with a GOx sensor that functions with a background electrode in which the background electrode has no GOx sensor (e.g., as discussed below in relation to <FIG> and <FIG>). The system may then compare the first signal and the second signal to detect ingestion of a medication by the user. The system may generate a sensor glucose value based on the comparison. In the embodiment illustrated in <FIG>, an op amp <NUM> or other servo-controlled device may connect to sensor electrodes <NUM> through a circuit/electrode interface <NUM>. The op amp <NUM>, utilizing feedback through the sensor electrodes, attempts to maintain a prescribed voltage (what the DAC may desire the applied voltage to be) between a reference electrode <NUM> and a working electrode <NUM> by adjusting the voltage at a counter electrode <NUM>. Current may then flow from a counter electrode <NUM> to a working electrode <NUM>. Such current may be measured to ascertain the electrochemical reaction between the sensor electrodes <NUM> and the biomolecule of a sensor that has been placed in the vicinity of the sensor electrodes <NUM> and used as a catalyzing agent. The circuitry (e.g., processing circuitry) disclosed in <FIG>, <FIG>, and <FIG> may be utilized in a long-term or implantable sensor or may be utilized in a short-term or subcutaneous sensor.

In a long-term sensor embodiment, where a GOx enzyme is used as a catalytic agent in a sensor, current may flow from the counter electrode <NUM> to a working electrode <NUM> only if there is oxygen in the vicinity of the enzyme and the sensor electrodes <NUM>. Illustratively, if the voltage set at the reference electrode <NUM> is maintained at about <NUM> volts, the amount of current flowing from the counter electrode <NUM> to a working electrode <NUM> has a fairly linear relationship with unity slope to the amount of oxygen present in the area surrounding the enzyme and the electrodes. Thus, increased accuracy in determining an amount of oxygen in the blood may be achieved by maintaining the reference electrode <NUM> at about <NUM> volts and utilizing this region of the current-voltage curve for varying levels of blood oxygen. Different embodiments may utilize different sensors having biomolecules other than a glucose oxidase enzyme and may, therefore, have voltages other than <NUM> volts set at the reference electrode.

As discussed above, during initial implantation or insertion of the sensor <NUM>, the sensor <NUM> may provide inaccurate readings due to the adjusting of the subject to the sensor and also electrochemical byproducts caused by the catalyst utilized in the sensor. A stabilization period is needed for many sensors in order for the sensor <NUM> to provide accurate readings of the physiological parameter of the subject. During the stabilization period, the sensor <NUM> does not provide accurate blood glucose measurements. Users and manufacturers of the sensors may desire to improve the stabilization timeframe for the sensor so that the sensors can be utilized quickly after insertion into the subject's body or a subcutaneous layer of the subject.

In previous sensor electrode systems, the stabilization period or timeframe was one hour to three hours. In order to decrease the stabilization period or timeframe and increase the timeliness of accuracy of the sensor, a sensor (or electrodes of a sensor) may be subjected to a number of pulses rather than the application of one pulse followed by the application of another voltage, for the second time period. In one embodiment, the first voltage may be <NUM> volts. In an embodiment, the first voltage may be <NUM> volts. In an embodiment, the first voltage may be approximately <NUM> volts.

<FIG> shows a flowchart of exemplary steps involved in modeling a relationship between glucose sensitivity and a sensor electrical property as a mosaic of models, in accordance with one or more embodiments. For example, process <NUM> may represent the steps taken by one or more devices as shown in <FIG>.

At step <NUM>, process <NUM> (e.g., using any circuitry described in <FIG>) partitions an input signal feature space. For example, process <NUM> may partition the input signal feature space into a plurality of contiguous subspaces. The input signal feature space comprises data about how a sensor device interprets the complex relationship between measured sensor electrical properties and interstitial glucose values and may include information about glucose sensitivity and/or sensor electrical properties associated with the sensor device, one or more sensor features and a complex calibration factor that represents the relationship between each measured sensor electrical property and its associated contribution to the expressed glucose measurement value from the sensor, or another information about the sensor device or a relationship between a sensor electrical property and glucose sensitivity. The input sensor feature space may comprise the complex relationship between sensor electrical properties, as captured by measured sensor data and interstitial glucose values. In some embodiments, coefficients of sensor features in a mathematical model may represent the calibration factor that relates the corresponding sensor feature to the contribution that feature makes to the final calculated interstitial glucose value. In some embodiments, glucose sensitivity may be measured by an interstitial current signal ("Isig") or another glucose sensitivity measurement. In some embodiments, the sensor electrical property may include wear time, battery life, calibration information, or another sensor electrical property of the sensor device. For example, process <NUM> may partition the input signal feature space according to certain ranges of the sensor electrical property for which glucose sensitivity behaves in a predicable manner. In some embodiments, process <NUM> may partition the input signal feature space according to sensor operating conditions (e.g., normal ranges, anomalous conditions, error states, etc.) based on signal characteristics (e.g., stability, regularity, consistency, etc.). Partitioning, for example, could result in one subspace associated with an operating condition characterized with typical analyte diffusion to the sensor and another subspace associated with reduced diffusion, which may be better served with a different glucose model. This partitioning may be created by partitioning the input signal feature space, by using sensor wear time and impedance. A complementary set of partitions may be defined through signal characteristics such as signals outside normal operating conditions or inconsistency in the signals.

At step <NUM>, process <NUM> (e.g., using any circuitry described in <FIG>) retrieves a machine learning model. For example, for each subspace, the system may train a machine learning model to predict glucose sensitivity. In some embodiments, process <NUM> may select a machine learning model based on a determination that the machine learning model is the simplest model available that provides accurate results. For example, the models may be tested from simplest to most complex. The models may be tested based on one or more criteria, such as accuracy, percent error, bias, target metrics, or any other criteria. If a particular model does not pass the test (e.g., based on the one or more criteria), the system may test the next model (e.g., a more complex model). For example, each of the criteria above may be associated with a threshold. In some embodiments, not passing the test may comprise satisfying the threshold or not satisfying the threshold. The system may proceed until the simplest model that passes the test is selected. In some embodiments, the predicted glucose sensitivity may be based upon a range of values associated with the sensor electrical property for the subspace. In some embodiments, process <NUM> may train the machine learning model using training data comprising clinical data on glucose sensitivity. In some embodiments, the training data for each subspace may be partitioned according to the plurality of contiguous subspaces before being fed into the plurality of models. In some embodiments, the training data for each subspace may be weighted according to the plurality of contiguous subspaces.

At step <NUM>, process <NUM> (e.g., using any circuitry described in <FIG>) receives sensor data from the sensor device. For example, the sensor device may provide sensor data on, for example, wear time, battery life, calibration information, electrical data, or other sensor electrical properties. At step <NUM>, process <NUM> (e.g., using any circuitry described in <FIG>) inputs the sensor data into the machine learning model.

At step <NUM>, process <NUM> (e.g., using circuitry described in <FIG>) receives an output from the machine learning model indicating glucose sensitivity of the sensor device. For example, the output may indicate a glucose sensitivity (e.g., glycemic range) of the sensor based on the sensor data. In some embodiments, process <NUM> may determine whether to blank the sensor based on the output from the machine learning model (e.g., as described below in relation to <FIG>).

At step <NUM>, process <NUM> (e.g., using circuitry described in <FIG>) may receive training data comprising clinical data on glucose sensitivity for a sensor device. In some embodiments, the clinical data may correspond to a sensor electrical property of the sensor device. In some embodiments, the sensor electrical property may include wear time, battery life, calibration information, or another sensor electrical property of the sensor device. In some embodiments, the training data for each subspace may be weighted according to the plurality of contiguous subspaces.

At step <NUM>, process <NUM> (e.g., using circuitry described in <FIG>) may partition the training data into a plurality of training data sets. In some embodiments, each of the plurality of training data subsets may correspond to one of a plurality of contiguous subspaces. In some embodiments, each of the plurality of contiguous subspaces may correspond to a range of values associated with the sensor electrical property for a respective subspace.

At step <NUM>, process <NUM> (e.g., using circuitry described in <FIG>) may train a respective machine learning model of the plurality of machine learning models to generate an output for blanking the sensor device based on each of the plurality of training data subsets.

It is contemplated that the steps or descriptions of <FIG> and <FIG> may be used with any other embodiment of this disclosure. In addition, the steps and descriptions described in relation to <FIG> and <FIG> may be done in alternative orders or in parallel to further the purposes of this disclosure. For example, each of these steps may be performed in any order or in parallel or substantially simultaneously to reduce lag or increase the speed of the system or method. Furthermore, it should be noted that any of the devices or equipment discussed in relation to <FIG> and <FIG> could be used to perform one or more of the steps in <FIG> or <FIG>.

<FIG> shows a machine learning model system for predicting glucose sensitivity based on sensor electrical properties of a sensor device, in accordance with one or more embodiments.

In some embodiments, the machine learning model system may include one or more neural networks or other machine learning models. As an example, neural networks may be based on a large collection of neural units (or artificial neurons). Neural networks may loosely mimic the manner in which a biological brain works (e.g., via large clusters of biological neurons connected by axons). Each neural unit of a neural network may be connected with many other neural units of the neural network. Such connections can be enforcing or inhibitory in their effect on the activation state of connected neural units. In some embodiments, each individual neural unit may have a summation function which combines the values of all its inputs together. In some embodiments, each connection (or the neural unit itself) may have a threshold function such that the signal must surpass the threshold before it propagates to other neural units. These neural network systems may be self-learning and trained, rather than explicitly programmed, and can perform significantly better in certain areas of problem solving, as compared to traditional computer programs. In some embodiments, neural networks may include multiple layers (e.g., where a signal path traverses from front layers to back layers). In some embodiments, back propagation techniques may be utilized by the neural networks, where forward stimulation is used to reset weights on the "front" neural units. In some embodiments, stimulation and inhibition for neural networks may be more free flowing, with connections interacting in a more chaotic and complex fashion.

In some embodiments, the machine learning model system may update its configurations (e.g., weights, biases, or other parameters) based on its assessment of the predictions. Memory may store training data and one or more trained machine learning models.

As an example, a machine learning model <NUM> may take inputs <NUM> and provide outputs <NUM>. In one use case, outputs <NUM> may be fed back (e.g., active feedback) to machine learning model <NUM> as input to train machine learning model <NUM> (e.g., alone or in conjunction with user indications of the accuracy of outputs <NUM>, labels associated with the inputs <NUM>, or with other reference feedback information). In another use case, machine learning model <NUM> may update its configurations (e.g., weights, biases, or other parameters) based on its assessment of its prediction (e.g., outputs <NUM>) and reference feedback information (e.g., user indication of accuracy, reference labels, or other information). In another use case, where machine learning model <NUM> is a neural network, connection weights may be adjusted to reconcile differences between the neural network's prediction and the reference feedback. In a further use case, one or more neurons (or nodes) of the neural network may require that their respective errors are sent backward through the neural network to them to facilitate the update process (e.g., backpropagation of error). Updates to the connection weights may, for example, be reflective of the magnitude of error propagated backward after a forward pass has been completed. In this way, for example, the machine learning model <NUM> may be trained to generate better predictions.

In some embodiments, inputs <NUM> may comprise sensor data associated with one or more sensor electrical properties of a sensor device, and reference feedback information <NUM> (which feeds back into machine learning model <NUM> as inputs) may include clinical data on glucose sensitivity. In this embodiment, the sensor data input may include the sensor signals, reference glucose information, model output, calculations based on these values, and labeled clinical data. In some examples, the clinical data may be labeled for training purposes. For example, the labels may be based on stability, regularity, or other properties of the sensor signals. (e.g., labeled as compliant/non-compliant with iCGM criteria, normal, anomalous, erroneous, etc.). For example, by reviewing the sensor data and reference glucose information, a label may indicate conditions where a typical model output would exceed the iCGM criteria, or a label may indicate a region where the sensor is not responding appropriately to changing glucose. Accordingly, when a particular value associated with a sensor electrical property of a sensor device is provided as input <NUM> to machine learning model <NUM>, machine learning model <NUM> may provide an output <NUM> including a prediction of glucose sensitivity of the sensor device.

In some embodiments, the system may partition the training data according to the same criteria used to partition the input signal feature space into a plurality of contiguous subspaces. For example, if the input signal feature space comprises twelve subspaces, the system may partition the training data into twelve subsets of data, producing one output estimate per subspace. In some embodiments, the system may partition the training data according to glucose sensitivity values, sensor features, or sensor electrical property values (e.g., according to the values used to partition the input signal feature space). In some embodiments, the partitioned training data may be used to train a model for each subspace, respectively.

In some embodiments, the entire training dataset may be used to train a model for each subspace, with the data corresponding to a particular subspace weighted more heavily when training that particular subspace. For example, the training data may be weighted according to the contiguous subspaces (e.g., based on the criteria used to partition the input signal feature space, as described above) and the training data corresponding to a particular subspace may be weighted more heavily when training a model for that particular subspace. In some examples, only the training dataset corresponding to a particular subspace will be used when training that particular subspace.

While machine learning model <NUM> is described in relation to the foregoing examples, it should be understood that machine learning model <NUM> may be trained to predict glucose sensitivity or any other quality of a sensor based on any sensor electrical property of a sensor device. In some embodiments, the outputs from machine learning model <NUM> may be utilized to determine whether to blank a signal (e.g., as described below in relation to <FIG> and <FIG>).

<FIG> shows a mosaic of models for modeling a relationship between glucose sensitivity and a sensor electrical property as a mosaic model <NUM>, in accordance with one or more embodiments. <FIG> shows a mosaic of models for modeling a relationship between glucose sensitivity and two sensor electrical properties as a mosaic model <NUM>, in accordance with one or more embodiments. In some embodiments, mosaic model <NUM>, as shown in <FIG>, and mosaic model <NUM>, as shown in <FIG>, may each comprise an input signal feature space. In some embodiments, the input signal feature space may comprise two or more dimensions.

As shown in <FIG>, axis <NUM> may represent a sensor electrical property or other sensor feature. For example, axis <NUM> may comprise wear time, battery life, or another measurement of time of a sensor device, calibration data of a sensor device, environmental properties (e.g., moisture) of a sensor device, or another sensor electrical property. In some embodiments, axis <NUM> may represent glucose sensitivity including but not limited to a maximum or minimum acceptable glucose measurement (e.g., based on iCGM criteria), a range of acceptable glucose measurements, a glycemic range, a calibration factor, or another measurement of glucose sensitivity.

As shown in <FIG>, axis <NUM> and axis <NUM> may each represent a sensor electrical property or other sensor feature. For example, axis <NUM> and axis <NUM> may each comprise one or wear time, battery life, or another measurement of time of a sensor device, calibration data of a sensor device, environmental properties (e.g., moisture) of a sensor device, or another sensor electrical property. In some embodiments, axis <NUM> may represent glucose sensitivity including but not limited to a maximum or minimum acceptable glucose measurement (e.g., based on iCGM criteria), a range of acceptable glucose measurements, a glycemic range, a calibration factor, or another measurement of glucose sensitivity. In some embodiments, these and other relationships may be modeled as a mosaic of models.

In some embodiments, the system may partition the input signal feature space to create mosaic model <NUM>, as shown in <FIG>, or mosaic model <NUM>, as shown in <FIG>. For example, the system may partition the input signal feature space into a plurality of contiguous subspaces. In some embodiments, to partition the input signal feature space, the system may identify subspaces of the input signal feature space within which glucose sensitivity behavior is the same or similar. For example, within certain ranges of the sensor electrical property (e.g., axis <NUM>, axis <NUM>, and axis <NUM>), the glucose sensitivity may behave in a predictable manner (e.g., linear behavior or another predictable behavior). The system may therefore partition the input signal feature space according to such ranges of the sensor electrical property (e.g., axis <NUM>, axis <NUM>, and axis <NUM>). In some aspects, the partitioning method is similar to clustering algorithms, where the features used for clustering result in multiple partitions or groups and where a single model dominates the output prediction. Therefore, unsupervised learning techniques, such as clustering algorithms may be used to create partitions using the described feature space. Other methods for identifying subspaces may be more accurate.

In some embodiments, to partition the input signal feature space, the system may identify stability of sensor trends, regularity of sensor signal magnitudes, or other characteristics of the sensor signal. Based on the aforementioned characteristics, the system may classify the sensor as normal, anomalous, erroneous, or another sensor operating condition. A normal operating condition may be one where a generic model performs well or where the model parameters match the general expectations. Conditions where the nearest model is biased, requires different predictors, or requires different predictor weights are commonly anomalous conditions. In contrast, erroneous operating conditions may be characterized with instability in the feature space components and high or unpredictable error in tuned models. The system may determine an optimal partition structure for each sensor classification. For example, the system may calculate improvements obtained from each partition structure in order to determine the optimal partition structure for the current application. The system may then partition the input signal feature space according to optimal partition structure. For example, the system may partition the input signal feature space as shown in <FIG> and <FIG> or into another partition structure. Additionally, in some embodiments, the system may determine methods for handling error conditions identified within the error range of the operating conditions.

In some embodiments, subspace partitions may be overruled for various reasons. For example, if one or more subspaces output an erroneous glucose sensitivity (e.g., based on percent error, bias, target metrics, or any other criteria), the system may determine alternate partitions for increased accuracy. In some embodiments, the system may compare a model in a particular subspace to models in adjacent subspaces. If the system identifies discrepancies or gaps between models in adjacent subspaces, the system may overrule the partitions (e.g., determine alternate partitions). In some embodiments, the system may compare outputs from a model of a particular subspace to a composite model based on the models of the entire input signal feature space. If the system identifies discrepancies between the model of the particular subspace and the composite model, the system may overrule the partitions (e.g., determine alternate partitions).

In some embodiments, the system may use a variety of models for modeling the relationship between glucose sensitivity and the sensor electrical property or other sensor feature. In some embodiments, different models may be used in each subspace. The models may include a linear regression model, a neural network, a machine learning model, or any other model. For example, in some embodiments, a plurality of models that may be used may be ranked from simplest to most complex. In some embodiments, it may be advantageous to use a simpler model when possible. Therefore, the models may be tested from simplest to most complex. For example, simpler models (e.g., linear models) may comprise fewer variables while more complex models may comprise more variables. The models may be tested based on one or more criteria, such as accuracy, percent error, bias, target metrics, or any other criteria. If a particular model does not pass the test (e.g., based on the one or more criteria), the system may test the next model (e.g., a more complex model). For example, each of the criteria above may be associated with a threshold. In some embodiments, not passing the test may comprise satisfying the threshold or not satisfying the threshold. The system may proceed until the simplest model that passes the test is selected. This process may be performed for each subspace. In some embodiments, simpler models may be sufficient for certain subspaces while more complex models are necessary for other subspaces. Therefore, a combination of different models may be used.

In some embodiments, the system may use various smoothing or blending techniques between models of contiguous subspaces. For example, partition boundaries may experience abrupt changes in glucose sensitivity. In order to smooth or blend the glucose sensitivity outputs around the boundaries, the system may extend the model for each subspace into the adjacent subspaces by predicting outside the subspace boundaries and by using training data outside subspace boundaries. Therefore, the area surrounding the boundaries of the subspaces may comprise several overlapping models. In some embodiments, the system may build a composite model based on the models of the entire input signal feature space. The system may overlay the composite model on top of the models of each subspace (e.g., overlaying the entire input signal feature space) and blend the composite model with the models of each subspace. In some embodiments, the system may use other methods of smoothing or blending the glucose sensitivity outputs at the subspace boundaries.

<FIG> shows a flow diagram <NUM> for input data to be transformed to sensor glucose values, in accordance with one or more embodiments. As shown schematically in <FIG> the methods and systems herein include: a sensor feature generator <NUM>, a blood glucose calibrator <NUM>, a sensor glucose modeler <NUM>, and a conditional blanker and terminator <NUM>. In some embodiments, the sensor glucose modeler <NUM> receives raw interstitial current signals, electrochemical impedance spectroscopy signals, and counter voltage signals and extracts the input features used by downstream machine learning models. The sensor glucose modeler <NUM> is responsible for applying machine learning techniques to convert the input signals into sensor glucose values. The blood glucose calibrator <NUM> is responsible for receiving input blood glucose values and adjusting the input sensor features from sensor glucose modeler <NUM> accordingly. The conditional blanker and terminator <NUM> applies various logic to determine when to stop displaying sensor output signals (e.g., remove, ignore, or forego to transmit the sensor data to the sensor device or any other device with a display interface) or terminate the sensor (e.g., stop transmitting sensor data from the sensor device) to reduce the probability of displaying noisy or erroneous information to the user or receiving output device. In some embodiments, input data (i.e., interstitially measured current (Isig), counter voltage (Vcntr), electrochemical impedance spectroscopy (EIS), and blood glucose calibration values (BG)) pass through the inventive algorithm to be transformed to sensor glucose values, or SG. The table below shows the information input and output from each of the four components.

The present invention improves upon current methods of sensor glucose modeler <NUM>. For example, the systems and methods described herein improve glucose sensitivity modeling by creating a mosaic of models of the relationship between glucose sensitivity and sensor electrical properties. The mosaic of models described herein may increase the accuracy of glucose sensitivity modeling.

In some embodiments, conditional blanker and terminator <NUM> may include or be associated with machine learning model <NUM>, as shown in <FIG>. For example, machine learning model <NUM> may determine glucose sensitivity of a sensor device based on one or more sensor electrical properties (e.g., as described above with reference to <FIG>). In some embodiments, acceptable ranges of glucose sensitivity of a sensor device may change as sensor electrical properties change. For example, as wear time of a sensor device increases, the sensitivity of the sensor device may decrease. The acceptable range of glucose sensitivity may therefore change dynamically with wear time (or another sensor electrical property). In some embodiments, glucose sensitivity may vary as sensor features change, for example, due to variability in the sensing environment, physiological dynamics, or sensor manufacturing. The mosaic of models described herein captures these dynamic changes and outputs a more accurate glucose sensitivity.

If a sensor device is not sufficiently sensitive for a particular sensor electrical property or sensor feature, the sensor device may be blanked. Conditional blanker and terminator <NUM> may determine whether to blank the sensor data (e.g., from a display interface) based on the output from machine learning model <NUM>. If the output from machine learning model <NUM> for a particular subspace indicates that the sensor device is not sufficiently sensitive (e.g., due to wear, time, calibration, sensing environment, physiological dynamics, sensor manufacturing, or other factors), conditional blanker and terminator <NUM> may blank the sensor device. For example, conditional blanker and terminator <NUM> may compare the output from machine learning model <NUM> with a glucose sensitivity threshold. If the output fails to satisfy the glucose sensitivity threshold, conditional blanker and terminator <NUM> may blank the sensor device. If the output from machine learning model <NUM> indicates that the sensor device is sufficiently sensitive, conditional blanker and terminator <NUM> may not blank the device. The mosaic of models within the input signal feature space may lead to more accurate outputs and therefore reduce the need for aggressive blanking and termination, allowing more precise blanking determination.

Claim 1:
A system for modeling a relationship between glucose sensitivity and a sensor electrical property, the system comprising:
memory configured to store a plurality of machine learning models (<NUM>), wherein each machine learning model of the plurality of machine learning models is trained using training data comprising clinical data on glucose sensitivity; and
a processor configured to:
partition an input signal feature space into a plurality of contiguous subspaces, the input signal feature space relating glucose sensitivity and a sensor electrical property associated with a sensor device (<NUM>);
receive sensor data relating to the sensor electrical property;
for each subspace, input the sensor data (<NUM>) into a machine learning model of the plurality of machine learning models based on a range of values associated with the sensor electrical property for the subspace; and
receive an output (<NUM>) from the machine learning model indicating glucose sensitivity.