Controller operation method and controller

Abstract

A method for controlling a wearable device that monitors a level of edema in a subject, the wearable device including a signal generator, two stimulating electrodes, and two sensing electrodes, includes generating, by the generator, a signal that causes a current to flow between the stimulating electrodes, and measuring impedance between the sensing electrodes placed on the subject's skin at time intervals during a test period, thereby providing impedance measurements; validating each impedance measurement against a model set of impedance measurements; and, if the measurement fails validation, excluding the measurement from the impedance measurements, thereby providing a subset of validated impedance measurements; converting each of the subset of validated impedance measurements to an edema index, thereby providing the edema index; averaging the edema indices to generate an average edema index for the test period; and generating an alert in response to the average edema index.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 038,700, filed June 12, 2020, which is incorporated herein by reference in its entirety.

[0002] Incorporation by Reference This application also incorporates by reference herein in its entirety the co-pending U.S. patent application Ser. No. 16 / 714,594, entitled "SYSTEMS AND METHODS FOR CALIBRATING DRY ELECTRODE BIOELECTRICAL IMPEDANCE SENSING," filed on December 13, 2019, and published as U.S. Patent Application Publication No. 2020-0187823.

[0003] FIELD OF THE INVENTION The embodiments described herein generally relate to methods and wearable devices for monitoring the level of edema in a subject. [Background technology]

[0004] Being able to measure physiological data in a non-invasive manner that results in high user compliance is important for continuous data collection to support numerous health monitoring applications. While devices are non-invasive and, in some cases, exist to passively monitor individuals over a period of time, balancing comfort with the necessary safe placement of sensors such as electrodes can create further obstacles to realizing the benefits of these physiological monitoring technologies.

[0005] Depending on the measurement in question, some physiological parameters are more difficult to measure than others, making data collection using non-invasive monitoring challenging. The challenges are particularly great when non-invasive monitoring is attempted for physiological parameters, which are inherently difficult to measure, subject to interference, and may rely on devices that may collect erroneous data along with useful data, introducing large amounts of erroneous data that overwhelm the collection of valuable data. Thus, the use of potentially valuable non-invasive monitoring devices requires the development and design of devices that prioritize the collection of valuable data while simultaneously discarding erroneous data, and methods of data acquisition that include retaining qualified data while removing other data that may be inaccurate or erroneous. Summary of the Invention [Means for solving the problem]

[0006] One or more embodiments provide wearable devices and methods for using such devices to monitor levels of edema, such as the level of hydration, fluid overload, or dehydration in an individual. The devices and methods measure changes in edema over time by various metrics, including absolute or relative measurements of edema, including measuring changes in the rate of change over time and assessing the impact of any of these metrics on physiological conditions. Such monitoring can be incorporated into other methods useful for critical monitoring situations, such as dialysis, chemotherapy, exercise programs, post-operative monitoring, and any other physiological condition that may involve the need for absolute or relative changes in edema levels or patterns that may indicate an underlying physiological condition manifested by excessive fluid retention or dehydration as reflected in edema measurements, which may predispose an individual to the development or progression of a number of adverse healthcare events, including infection, high blood pressure, kidney disease, heart disease, etc. Monitoring edema levels may also be useful in long-term scenarios for individuals with chronic heart failure, chronic kidney disease, and similar conditions where subtle changes in absolute or relative measurements of edema may be the best indicators of disease progression or remission. The devices and methods described herein are preferably passive, i.e., do not require active input from the individual or invasive monitoring that requires penetrating the skin or taking a biological sample from the patient.

[0007] Wearable devices are designed to comfortably contact the skin of an individual being monitored and acquire impedance measurements that can be converted into an edema index. In such devices, the wearable device's failure to tightly constrict around the patient's skin, for example to avoid uncomfortable restriction of blood flow or uncomfortable binding, can result in inaccurate data or an over-inclusion of inaccurate or erroneous data along with valuable data, making it impossible to distinguish between clinically useful data for treating the patient and data that confounds the diagnosis. However, the use of the devices and methods for collecting and analyzing data described herein require that the devices and data storage and processing capabilities acquire an adequate number of data points with a high level of confidence, particularly including impedance values ​​over the test period, and require the ability to remove inaccurate data points through a validation process. Thus, developing and processing accurate data requires the identification and removal of erroneous or invalid data that can be appropriately excluded for medical or physiological reasons from the larger group of measurements used to calculate the edema index, which may represent a variety of physiological conditions, including, but not limited to, a data set representing an individual's hydration level.

[0008] A method for monitoring absolute or relative levels of edema in a subject is provided, along with necessary data processing and analysis steps, including, but not limited to, measuring changes in absolute or relative impedance values ​​between at least two electrodes placed at different points on a skin region of a subject's extremity, both in absolute terms and over time, and the rate of change of an edema index calculated as follows: The set of measurements may be repeated at selected time intervals during a test period, including individual and separate test periods based on an identified calibration test and protocol, and may consist of providing multiple impedance measurements, along with control and calibrated reference values. Each measurement is validated against a model set of impedance measurements collected during either the test, calibration, or control period.

[0009] The method includes determining whether any impedance measurements included in any test, control, or calibration protocol fail a validation process, which may exclude individual data points or sets of data points, thereby identifying erroneous or invalid data and removing it from the plurality of impedance measurements to provide a subset of validated impedance measurements. Each of the set or subset of validated impedance measurements is converted to an edema metric, including any of the calibrated edema indices described below, resulting in either an individual or multiple edema indices derived from the absolute or relative levels or patterns of the impedance measurements. The multiple edema indices may be subjected to mathematical processing, including measurement of the mean, mode, median, threshold, or mathematical or statistical measure, to generate a particular edema index over the baseline establishment, testing, or calibration period. In some variations, approximately 10%, 20%, 30%, 40%, or more of the multiple impedance measurements may fail validation and may be removed from the subset or final set of impedance values ​​that form the set or subset of validated impedance measurements. In some variations, the subset of verified impedance measurements may include at least 40% of the plurality of impedance measurements taken during the test period.

[0010] Impedance measurements may be repeated about every 1 minute, about every 10 minutes, about every 20 minutes, about every 30 minutes, about every 60 minutes, or about once every 24 hours, or any time period therebetween. Impedance measurements may be performed for about 50 milliseconds, about 1 second, about 2 seconds, about 3 seconds, about 4 seconds, or any time period therebetween. In some variations, the test period may be from about 1 hour to about 48 hours, or any time period therebetween.

[0011] In some variations, the model set of impedance measurements may include a Cole-Cole model. Validating each of the plurality of impedance measurements may include fitting and evaluating an individual selected set or subset of the impedance measurements against a Cole-Cole model of impedance measurements. The Cole-Cole model provides R, R inf , f char The quality of the fit of individual impedance measurements to the Cole-Cole model provides another measure of data quality, and measurements with significantly worse fits than the baseline expectations can be excluded from the analysis. Examples of these measures include the total error term from the expectation given by the Cole-Cole model, the number of frequency points above a threshold from the expected fit, the overall shape of the data relative to the Cole-Cole fit, the relationship of a given impedance measurement's Cole-Cole derived edema index to edema indices from similar bioimpedance measurements (where the similarity is determined by temporal proximity or by Cole-Cole features, e.g., edema metrics R, R). inf , f char and proximity under some measure in a distance space defined by a combination of metadata about the sweeps, such as time, and features derived from the raw sweeps themselves, such as the variance of the phase shift of the impedance signal.

[0012] The method may further include recording an average edema index over the test period. Measurements may be taken over an extended period, which may be at least one day and may extend for six months or more. In some variations, a specific statistical or mathematical calculation of an edema metric or index may be recorded for each period of the extended test.

[0013] In some variations, the method may include outputting or transmitting an alert when a selected edema metric exceeds a preselected value or range of values. In another variation, the method may further include outputting or transmitting an alert when the edema metric falls below a preselected value or threshold. The alert may be an electronic report to the patient, caregiver, or healthcare provider. In some variations, the alert may be an audible or visual report and may include data assembled by the wearable device or data processed according to a method for using such a device.

[0014] In some variations, the different locations of the at least two electrodes may be at least 1 centimeter apart on the subject's skin or may be placed anywhere on the individual's body, including configurations where the electrodes are spaced apart enough that they are placed on opposite limbs, for example, one electrode on the left foot and the other on the right wrist.

[0015] In some variations, the method further includes fastening one or more bands including at least two electrodes to a limb of the subject, thereby positioning the at least two electrodes at different points on the skin of the subject. In some variations, the limb may be the subject's wrist or the subject's leg.

[0016] In any of the methods and devices described herein, impedance measurements (sometimes referred to as bioelectrical impedance measurements) may be made by measuring the electrical properties of biological tissue using one or more pairs of sensing electrodes and determining absolute, relative, or calibrated impedance measurements from an applied forward current, in which a current is passed between a pair of stimulating electrodes in a forward direction, and an applied short-circuit current, in which the same current is passed simultaneously through both stimulating electrodes. The voltage at the sensing electrodes during both forward (e.g., forward current) and short-circuit (e.g., short-circuit current) operation, and the current or voltage at the current-sensing resistor during forward operation, may provide a calibrated impedance measurement for the tissue. Sensing bioimpedance using this self-calibrating measurement, in this case using a "short-circuit" current to calibrate the forward (and / or, in some variations, reverse) current, may provide highly accurate and reproducible results. The short circuit current may be supplied before or after the forward (and / or reverse) current, or may be supplied immediately or shortly thereafter (e.g., within milliseconds, seconds, or minutes) after the forward (and / or reverse) current. The same current (e.g., same amplitude, frequency, duration, etc.) may be supplied in the short circuit configuration as in the forward and / or reverse current configuration(s). In some variations, one or more characteristics (e.g., amplitude, frequency, duration, etc.) of the short circuit current may differ from the forward and / or reverse current.

[0017] For example, a method for determining bioelectrical impedance may be referred to as "calibrated bioelectrical impedance" and may include: in a forward mode, supplying a first current between a source electrode and a sink electrode and storing voltages from the first and second sensing electrodes; in a short-circuit mode, simultaneously supplying a second current to both the source and sink electrodes and storing voltages from the first and second sensing electrodes; and outputting a calibrated bioelectrical impedance measurement, wherein the bioelectrical impedance measurement is based at least in part on the voltages of the sensing electrodes in both the forward mode and the short-circuit mode. The first and second currents may have the same amplitude, frequency, and / or duration, or may be recognized, coordinated, and set to predetermined values ​​in subsequent data processing steps. The first and second currents may be supplied within a predetermined time of each other (as close as 100 microseconds to as long as an hour apart). The first and second currents may be supplied substantially immediately after each other. The method may include cycling between modes (eg, between forward and short circuit modes, or between forward, eg, standard, short circuit, and reverse modes).

[0018] Estimating the calibrated bioelectrical impedance measurement may include determining the calibrated bioelectrical impedance measurement based at least in part on a voltage difference between the first sensing electrode and the second sensing electrode in both the standard mode and the short-circuit mode, a ratio of the voltages at the first sensing electrode in the standard mode and the short-circuit mode, and a current through the current sensing resistor in the standard mode. [Brief explanation of the drawings]

[0019] [Figure 1] 1 is a graphical representation of a wearable device according to some embodiments of the present disclosure. [Figure 2] FIG. 1 is a block diagram of a wearable device according to some embodiments of the present disclosure. [Figure 3] FIG. 10 is a block diagram illustrating a forward signal path through a sensing electrode of a wearable device, according to some embodiments of the present disclosure. [Figure 4] FIG. 10 is a block diagram illustrating a reverse signal path through a sensing electrode of a wearable device, according to some embodiments of the present disclosure. [Figure 5] FIG. 10 is a block diagram illustrating a short-circuit signal path through a sensing electrode of a wearable device, according to some embodiments of the present disclosure. [Figure 6] FIG. 1 is a schematic diagram of a five-element circuit model for bioimpedance measurements. [Figure 7] 1 is a graphical representation of a Cole-Cole plot for bioimpedance. [Figure 8] 1 is a flowchart of a monitoring process performed in accordance with some embodiments of the present disclosure. [Figure 9] 1 is a graphical representation of bioimpedance measurements over time. [Figure 10A] 1 is a graphical representation of a least squares fit of bioimpedance measurements plotted against the volume of fluid extracted. [Figure 10B] 1 is a graphical representation of a least squares fit of bioimpedance measurements plotted against the volume of fluid extracted. [Figure 11] FIG. 1B is a circuit diagram corresponding to the forward and reverse signal paths of a wearable device according to some embodiments of the present disclosure. [Figure 12] FIG. 10 is a circuit diagram corresponding to a shorted signal path in a wearable device according to some embodiments of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0020] Physiological monitoring can be an important part of health care for individuals suffering from chronic diseases, such as, but not limited to, heart failure (which may also be called congestive heart failure (CHF)). In many diseases, monitoring hydration levels, such as edema and / or dehydration, can provide early notification of changes in an individual's physical condition. Such early notification of adverse changes in hydration levels can provide an opportunity for early intervention. Opportunities for early intervention may result in fewer drastic adjustments to medications, dialysis therapy, or personal care, instead of a delayed response to more catastrophic changes in the individual's condition. In addition to the obvious benefits to the individual, preventing serious deterioration also has cost benefits for home care or outpatient care settings.

[0021] For example, a heart failure patient may exhibit increasing edema as the disease accelerates or progresses from a chronic to an acute state, and a given change in edema metrics may indicate a change in pharmaceutical, behavioral, or even surgical intervention. The ability to intervene with more limited changes in diuretic administration or the introduction of other medications without interfering with the effectiveness of other medications an individual may be using to control other illnesses may provide more stable supportive care. This is particularly important for elderly patients, who are often balancing care for multiple illnesses, and changes in absolute or relative levels of the edema index may provide important information regarding changes in one or more underlying disease states.

[0022] In another example, monitoring hydration levels can be important when post-operative patients are discharged to home or rehabilitation centers with less intervention from medical professionals to ensure they do not become dehydrated, which can make them vulnerable to serious post-operative secondary infections.

[0023] For these and other situations, physiological monitoring over a specific period of time, such as during a dialysis session for a patient with renal failure, or for less specific durations, such as for a patient with heart failure, may be advantageous. The use of a monitoring device that requires little or no input / assistance from the individual may be highly advantageous. Furthermore, the device may require less close contact with the individual to enhance comfort and compliance for individuals in home care settings or post-operative patients. The device may also require the elimination of certain features that typically provide high efficiency, such as hydrogel pads, which provide skin-to-electrode contact and are often used in clinically used monitoring devices. Consequently, measurements obtained by physiological monitoring devices may be affected by individual movement and therefore may not be accurate or useful. Therefore, the ability to separate erroneous or inaccurate data from valuable data under less-than-perfect physiological monitoring conditions is a valuable aspect of the present invention.

[0024] Therefore, a method for edema monitoring should be able to test and reject data points or data sets that are erroneous, inaccurate, or do not provide usable monitoring data. While devices worn for long periods of time may provide such erroneous data, as discussed above, continuous operation of the device for long-term data collection may provide the offsetting advantage of obtaining a large number of data points that can be subsequently tested to determine which data should be included in obtaining edema and / or dehydration measurements and which data should be rejected as inaccurate or erroneous.

[0025] Bioelectrical impedance analysis measures the bioimpedance of biological tissues generated within an individual's body parts that are susceptible to the flow of alternating current. Bioimpedance is a function of tissue properties and the frequency of the applied current signal. The human body contains several different components that contribute to these measurements, including minerals (such as those found in bone and electrolytes), muscle, lean tissue mass, and body water, which is divided into intracellular and extracellular water. Furthermore, distinct intracellular structures may also contribute to the edema index and may be separable from the intracellular and extracellular measurements or processed using separate statistical metrics as part of the analytical methods described herein.

[0026] Because cell membranes are inherently capacitive, the capacitive reactance generated by electrical current allows current to pass through such structures, individually or collectively, depending on the signal frequency and, therefore, the current path. Low-frequency currents pass through the extracellular fluid because cell membrane reactance does not allow them to pass through such structures, whereas high-frequency currents penetrate the cell membrane and pass through both the extracellular fluid and the cell (membrane and intracellular fluid). Therefore, by applying an alternating current at a specific frequency, bioimpedance measurements can assess the amount of extracellular water (ECW), intracellular water (ICW), and total body water (TBW = ECW + ICW). In this way, measurements of edema and / or dehydration can be obtained.

[0027] Provided herein are methods for using a wearable device to monitor levels of edema and / or dehydration, and more generally, the hydration level of an individual, which may be obtained from measurements of impedance across the individual's entire body.

[0028] A wearable device may have any number of drive, sense, or combined drive / sense electrodes, and two drive points and two sense points may be selected. A wearable device with a two-electrode configuration injects a current signal and performs voltage measurements at the same electrode. Therefore, the impedance measured with a two-electrode device includes the voltage drop due to contact impedance. In a wearable device with a four-electrode configuration, two separate electrode pairs are used for current injection and voltage measurement; a constant-amplitude current signal may be input through two external electrodes (e.g., current or drive electrodes), and a frequency-dependent voltage signal may be measured at two points via two internal electrodes (e.g., voltage or sense electrodes). In either case, the wearable device may be configured to measure impedance between two electrodes placed at different locations on an individual's limb. The individual's limb may be an arm or a portion of the arm, such as the wrist, or a leg or a portion of the leg, such as the ankle. In some variations, the wearable device is configured to be secured to an individual's wrist, so that two electrodes that sense voltage (e.g., convertible into an impedance measurement) are placed at two different points on the individual's skin. The two points can be separated by at least 10 mm from each other, or as far as the wearing subject's physiology allows. The sensor electrodes are localized to read the difference in area between the two sensing electrodes. The detected voltage can be converted to impedance (Z), which represents a measure of hydration in the body part through which the input current passes. In the methods provided herein, the impedance can be related to an edema index for monitoring an individual.

[0029] Figure 1 shows one non-limiting example of a suitable wearable device 100. The bioelectrical measurement wearable device 100 of Figure 1 is shown engaged on an individual's wrist 102, with the wearable device 100 in contact with the individual's skin 104. The wearable device 100 includes internal electronics 106 connected to electrodes 112, 114, 116, and 118 in contact with the skin 104. The first electrode 112 and the third electrode 116 are stimulating electrodes. The second electrode 114 and the fourth electrode 118 are sensing electrodes. The electrodes are all dry contact electrodes and do not require skin conditioners, gels, or other materials to optimize skin-electrode impedance.

[0030] The wearable device 100 may be electronically connected to other devices, such as processors, medical records, or databases, and data may be processed locally within the device or in a nearby or remote processor. The wearable device 100 may be further configured to provide a visual signal when battery power is low. The wearable device 100 may be further configured to provide a visual or audible alert when measurements exceed and / or fall below preselected thresholds, as verified as described below. To achieve these functions, the wearable device 100 may have one or more lamps, such as LEDs, a display, such as a liquid crystal display (LCD), and / or a speaker (not shown in FIG. 1 ).

[0031] FIG. 2 is a block diagram of the wearable device 100. As shown in FIG. 2, the internal electronics 106 of the wearable device 100 include a controller 200, a signal generator 202 for generating test signals, a signal processor 204 for processing signals transmitted or received via the electrodes 112, 114, 116, and 118, an optional multiplexer 206 for multiplexing and routing the signals, a power source 208 for power supply such as a battery, and a current sensing resistor 210 for sensing current. For example, the current sensing resistor 210 is electrically connected to one of the lines between the signal processor 204 and the multiplexer 206 to sense the current flowing therebetween. The controller 200 may include one or more processors and volatile and nonvolatile memory. The controller 200 may further include an interface circuit configured to communicate with an external device, such as a host computer, and output alerts and related data via a wired or wireless network. In some variations, any of these components may be combined or integrated together. Characterization of the skin-electrode interface may be achieved by routing the test signal generated by the signal generator 202 through the stimulation electrodes 112 and 116 in a forward or short-circuit configuration (and, in some variations, a reverse configuration) via an optional multiplexer 206 or other control and / or switching circuitry, as described and shown below in Figures 3-6.

[0032] For example, Figure 3 shows an example of operation of the wearable device 100 shown schematically in Figure 2 in a forward configuration. In the forward configuration, the controller 200 is configured to operate the wearable device 100 such that the signal 15 generated by the signal generator 202 may be passed and / or processed by the signal processor 204 and routed forward between the source electrode 112 and the sink electrode 116 by the multiplexer 206. When a current is passed between the source electrode 112 and the sink electrode 116, the controller 200 may detect signals from the sense electrodes 114, 118. In this example, data signals 16A and 16B may be processed and interpreted by the signal processor 204 and the controller 200. These data signals may correspond to the voltage(s) at the sense electrodes 114 and 118. Simultaneously, the signal (e.g., voltage and / or current) from the current sensing resistor 210 (not shown in FIGS. 3-5) may be recorded during application of the forward signal, and the resulting forward characteristic data 17 may be stored in a memory (not shown) of the controller 200 as shown in FIG. 2.

[0033] Following operation of the wearable device 100 in the forward configuration for one or more sets of samples (e.g., recording at one or more frequencies, etc.), the wearable device 100 may be automatically switched (e.g., by action of the controller 200) to operate in the short-circuit configuration. Alternatively or additionally, the wearable device 100 may be configured to switch to operate in a reverse configuration, in which the source and sink electrodes 112, 114, 116, and 118 may be reversed (e.g., the source may operate as a sink, and the sink may operate as a source), as shown in FIG.

[0034] Figure 4 shows an example of the operation of the wearable device 100 shown schematically in Figure 2 in a reverse configuration. In Figure 4, signal 19 generated by signal generator 202, which may be the same or different from signal 15 applied in the forward configuration, may be processed by signal processor 204 and sent by multiplexer 206 in the reverse direction between sink electrode 116 and source electrode 112. Sense electrodes 114 and 118 may be used to record data signals 20A and 20B (e.g., voltage) resulting from the reverse current; these sensed data signals, along with the sensed current and / or voltage from current sense resistor 210, may be processed and interpreted by signal processor 204 and controller 200; and the resulting reverse or second characteristic data 21 may be stored by controller 200 as shown in Figure 2.

[0035] As described above, immediately after one or more operations of the wearable device 100 in the forward and / or reverse configurations or modes, the wearable device 100 may be automatically switched (e.g., by action of the controller 200) to operate in a short-circuit configuration, in which current is simultaneously sent to both the source electrode 112 and the sink electrode 116. In the short-circuit configuration, or short-circuit mode, the same current may be supplied to both the source electrode 112 and the sink electrode 116. The supplied current may be the same or approximately the same as that supplied during the forward and / or reverse configurations. In some variations, the current may be different; for example, the current supplied to both electrodes when operating in the short-circuit configuration may be less than during operation in the forward and / or reverse configurations.

[0036] FIG. 5 illustrates an example of the operation of the wearable device 100 described above in a short-circuit configuration / mode. In FIG. 5, parallel signals 24 (e.g., current) generated by the signal generator 202 may be processed by the signal processor 204 and routed by the multiplexer 206 in the parallel or short-circuit direction, whereby the same signal (e.g., current) is provided to both the source electrode 112 and the sink electrode 116. Signals sensed by the sensing electrodes 114 and 118 resulting from the provided signals may be received as data signals 25A and 25B and processed and / or interpreted by the signal processor 204 and the controller 200. The signals received during the short-circuit operation (e.g., voltages at the sensing electrodes 114, 118) may correspond to short-circuit characteristic data 26 and may be stored by the controller 200 as shown in FIG. 2.

[0037] In some variations, the controller 200 uses the forward data 17 and the short-circuit data 26 (and / or, in some embodiments, the reverse data 21 and the short-circuit data 26) to characterize the interface 27 between the electrodes 112, 114, 116, and 118 and the skin to determine an accurate estimate of the bioelectric signal (e.g., bioelectrical impedance) of the tissue (i.e., the skin in contact with the electrodes).

[0038] Using the wearable device 100 described above, impedance measurements can be taken frequently, providing multiple impedance readings, which can range from as few as 10 measurements to many more (e.g., thousands) over a selected test period. Measurements can be taken at selected time intervals during the test period. Impedance measurements can be repeated as frequently as once every minute to once every 48 hours. Impedance measurements can collect data between 500 μs and 450 s.

[0039] Measurements may be collected over a test period, which may be about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 16 hours, about 18 hours, about 24 hours, or any value therebetween. In some variations, the test period may be about 1 hour to about 24 hours. Measurements obtained during the test period may be grouped to obtain an average value of the measurements or other statistical grouping deemed to provide meaningful information to a caregiver, such as a daily average value of the measurements. Grouped measurements may be expressed as an edema index or hydration value and may be included in the individual's record and retained for the period during which the measurements were taken.

[0040] Measurements may be grouped for shorter test periods, e.g., daily, as a non-limiting example, but may also be continued over longer periods to monitor an individual. The period for which monitoring is provided may be as short as one, two, or several days, such as when monitoring an individual undergoing kidney dialysis. In another variation, for example, when monitoring an individual with heart failure, the period for which monitoring is provided may be about one week, about one month, about two months, about three months, about six months, or a year or more. In some variations, monitoring may be provided for about one month to about six months or longer. Average values ​​(or grouped values) from each test period may be recorded over the entire monitoring period. In some variations, the recorded value may be an average edema index rather than an impedance value.

[0041] In some variations, an alert may be output or transmitted from the wearable device 100, the external device to which the wearable device is connected, or the external device storing the database to which the grouped or averaged measurements are transmitted, when the averaged / grouped measurements exceed or fall below a preselected threshold. The alert may notify the patient, healthcare provider, or caregiver that intervention may be necessary or that more involved monitoring may be required for the individual. In some variations, the alert may further include a visual or audible alert issued from the wearable device 100, the external device to which the wearable device 100 is connected, or the external device storing the database to which the grouped or averaged measurements are transmitted. Thus, the data analysis device and method may be integrated with companion devices carried by patients, such as cell phones, computers, and other mobile monitoring devices, as well as with institutional networks employed by hospitals for localized or distributed monitoring of patients with chronic or critical care conditions.

[0042] As noted above, individual impedance measurements may be or include erroneous factors because the wearable device 100 is not attached uncomfortably to the individual's body part and the electrodes do not have hydrogel or other skin conditioning agents to aid in electrical measurements. Additionally, the individual is not required to maintain a restrained or fixed position. Under any of these conditions, the wearable device 100 may slip or move, resulting in erroneous measurements. This may cause the wearable device 100 to verify any or all of the impedance measurements.

[0043] Impedance measurements may be made at a single frequency or at multiple frequencies, which may range from about 1 kHz to about 1 MHz, or any single or multiple frequencies therebetween.

[0044] Impedance measurements can be validated against a model of bioimpedance, which can be chosen to be a five-element circuit model, as shown in Figure 6. In this model, r1 represents the extracellular fluid, and the other branches represent the intracellular components of the aqueous fluid containing structures. C1 represents the cell membrane, r2 represents the intracellular (cytoplasmic) fluid, C2 represents the intracellular membrane, and r3 represents the corresponding fluid within the intracellular structures (e.g., nucleus, lysosomes, etc.) surrounded by the intracellular membrane. In some variations of these techniques, the C2-r3 branch of this circuit can be ignored and modeled through adjustment of the C1 and r2 values.

[0045] Each data point, or any selected subset of them, can be fitted to a Cole-Cole model as shown in FIG. 7, using the following relationship:

number

number

[0046] However, a data point or set of data points that does not produce a good fit to the Cole-Cole plot may be excluded from the plurality of impedance measurements, thereby providing a subset of validated impedance measurements. In some variations, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, or more of the impedance measurements obtained during the test period may fail to be validated, such as failing to fit a Cole-Cole plot.

[0047] Each of the verified impedance measurements may then be used to calculate an edema index for the individual using a combination of values ​​derived from the formula. An example of an edema index is R o Another example is the relation:

number

[0048] This allows the wearable device 100 to provide multiple edema indices for each test period, which may be averaged in any suitable manner to provide an average edema index for the test period. The advantage of this method is that a large number of impedance measurements can be obtained without input from the monitored individual, and a proportion of impedance measurements that do not fit a Cole-Cole plot can be excluded. In some variations, the validated measurements may be greater than about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or more of the impedance measurements taken during the test period. The resulting edema metrics, including but not limited to the average edema index for the test period, correlate with the individual's hydration status, even when there are many data points that could not be included due to movement of the wearable device 100 over the individual's skin, as shown in FIG. 9 and further described below.

[0049] The test period may be, for example, 24 hours, and the monitoring period may be several days or many days, and the average edema index may be used to track the edema level (or hydration level) of the individual being monitored by the wearable device 100.

[0050] 8 is a flowchart showing steps of a monitoring method performed by the wearable device 100. First, the controller 200 controls the signal generator 202 to generate a test signal, which causes specific currents at various frequencies to flow between the stimulating electrodes 112 and 116 placed on the skin of the subject's limb, e.g., the arm, and measures the impedance between the two sensing electrodes 114 and 118. The measured impedance may be stored in a memory (not shown) of the controller 200.

[0051] In S502, the controller 200 validates the impedances measured in S501 by determining whether each impedance fits the Cole-Cole model. For example, the controller 200 determines that one or more of the measured impedances that fall within a specific range for the Cole-Cole plot shown in FIG. 7 fit the Cole-Cole model. In S503, the controller 200 excludes the measured impedances that were not validated in S502 from subsequent analysis. In S504, the controller 200 converts the validated impedances into an edema index. For example, the conversion may be performed based on Equation 3 above. Subsequently, the controller 200 calculates an average value of the edema index in S505 and outputs the average edema index in S506, for example, by storing the index in memory. The controller 200 may transmit the calculated edema index to an external device via a network interface (not shown).

[0052] All steps shown in Fig. 8 may be performed by the wearable device 100. Alternatively, one or more of S503 to S506 may be performed by an external device connected to the wearable device 100. In this case, the controller 200 transmits the measured impedance to the external device via the interface circuit. The steps shown in Fig. 8 may be repeatedly performed during a selected test period.

[0053] Example Experiment 1. Long-Term Individual Monitoring. Subjects were passively monitored over a 15-day period with wearable device 100, collecting impedance measurements over 10-20 minutes at selected times each day, as shown in FIG. 9. Data was collected while the individual was awake and was not evenly distributed throughout each 24-hour period. Data was validated against the Cole-Cole model as described above. Data that did not validate are essentially shown within regions 401-426. Only valid data points were used for conversion to an edema index, which was then averaged to produce an average edema index for each period (i.e., each day). The average daily edema index is shown as line 450 for days 1-15.

[0054] As can be seen in Figure 9, the mean edema index value, shown by line 450, decreases from day 1 (i.e., the mean edema value at point 455) as the individual contracts the flu. The mean edema index decreases with increasing dehydration due to the flu at day 9, point 460, and is low at day 12, point 465. As the individual recovers, the mean edema index also recovers, as shown at day 15, point 470.

[0055] Experiment 2. Edema Measurement During Dialysis. A group of individuals undergoing dialysis were fitted with the wearable device 100 and monitored during a 3-hour dialysis session. Measurements were taken every 10–20 minutes and fit to the Cole-Cole model described herein. Each panel in Figures 10A and 10B shows an individual dialysis session for one individual. The panels show the passage of time along the X-axis, with the volume of water extracted (liters, L) decreasing from a value of 0.00 to the final volume extracted (i.e., the intersection of the left Y1 axis and the X-axis) from time t = 0 to 3 hours. The Y1 axis shows the reversal of ultrafiltration recorded during the dialysis session. The individual's hydration level, measured by the method described herein, is shown on the right Y2 axis and decreases from a value of 1.00 to the final value at t = 3 hours. The right Y2 axis shows the R value immediately after the start of the dialysis session divided by each R value during the dialysis session (i.e., normalized resistance). For illustrative purposes, only the Y2 axis graph is labeled "R" in each panel. The least-squares value R represents the goodness of fit. 2 ranges from a high of 0.973 to a low of 0.135.

[0056] As shown in the set of graph panels in Figures 10A and 10B, although the correspondence from individual to individual and from dialysis session to the next did not reach perfect correspondence, across the set of individual measurement sessions, R 2 An overall value of 0.752 was obtained, indicating substantial correspondence across the groups.

[0057] Bioelectrical Impedance Calibration As mentioned above, the short circuit configuration of the wearable device 100 shown in Figure 5 may be used to calibrate bioelectrical impedance. Such calibration may be performed, for example, during or after the impedance measurement shown in Figure 8.

[0058] The impedance mismatch between the subject's skin 104 and the sensing electrodes 114, 118 may be determined by the controller 200 of the wearable device 100 during calibration and used to adjust the interpretation of the bioelectric signals from the electrodes 114, 118. The wearable device 100 performs a set of calibration measurements. For example, the calibration measurements may include the differential voltage between the sensing electrodes 114, 118, the total current through the electrodes 114, 118 (e.g., the current through the current sense resistor 210), and the voltage at the input of one of the sensing electrodes 114, 118 in the forward (or reverse) and short-circuit configurations. Any suitable set of measurements may be used to calibrate the impedance of the electrode / skin interface 27.

[0059] For example, as described above, a first set of measurements may be made with current flowing in either the forward or reverse direction to provide forward data 17 or reverse data 21. Short-circuit data 26 may be collected as described above (e.g., immediately after, before, or intermittently after collecting data from the forward and / or reverse configurations), and the first set of data, e.g., forward data 17 and short-circuit data 26, may be combined to calculate a first impedance of the subject's tissue that is calibrated through use of the short-circuit data.

[0060] In some variations, the measurement and calculation process may be repeated using a previously unused current direction (e.g., reverse data 21) and corresponding short-circuit data 26. The reverse data 21 and short-circuit data 26 may be combined to calculate a second impedance of the subject's tissue. The first impedance data may then be combined with the second impedance data, for example, by averaging the two together, weighting the forward direction with the reverse direction, etc., which may improve the accuracy of the resulting bioelectrical impedance measurements.

[0061] In particular, bioelectrical impedance may be calibrated by the differential voltage at the sensing electrodes 114 and 118 and the ratio of the voltage at the input to one of the sensing electrodes 114 and 118 between both the forward and short-circuit configurations.

[0062] For example, Figures 11 and 12 depict schematic diagrams of the operation of the wearable device 100 shown in Figures 2-5 in a normal forward configuration and a short-circuit configuration, respectively. In Figures 11 and 12, the current source / sink electrodes 112 and 116 have impedances Z1 and Z3, respectively. The voltage sensing electrodes 114 and 118 have impedances Z4 and Z5, respectively. The subject's tissue has impedance Z2, and the current sensing resistor 210 has impedance Z6. Z8 and Z9 refer to the input impedances to the buffer amplifier. As noted above, Figure 11 depicts the system in a forward configuration or mode, while Figure 12 depicts the system operating in a short-circuit configuration or mode, in which current is passed through both the source electrode 112 and the sink electrode 116 simultaneously.

[0063] As described above, the wearable device 100 has a source electrode 112 and a sink electrode 116, and at least two sense electrodes 114 and 118. The wearable device 100 also has the ability to switch between a forward or standard configuration and a short-circuit configuration, and in some variations, a reverse configuration. Thus, the wearable device 100 not only directs current in the forward (and / or reverse) direction, but also directs current through both the source electrode 112 and the sink electrode 116 simultaneously, allowing for measurement of leakage currents I8 and I9, shown in FIGS. 11 and 12, through the sense electrodes 114 and 118.

[0064] In this manner, the wearable device 100 may be configured to measure the differential voltage at the sense electrodes multiplied by the amplifier gain (G(V4-V5))=β. In the standard (forward) configuration, the differential voltage at the sense electrodes multiplied by the gain may be denoted by the subscript "N". In the short-circuit configuration, the differential voltage at the sense electrodes multiplied by the gain may be denoted by the subscript "B". Thus,

number

number

[0065] The differential voltage across the current sense resistor 210 is (G(V6-V7))=α. Therefore, for the forward configuration:

number

[0066] The various gains described above may be set to be the same gain (e.g., the gain for the amplifier used) or they may be different gains, and for convenience these gains are shown herein as being the same gain, but it should be understood that they may be different.

[0067] The voltage at the input of one of the sensing electrodes 114 and 118, e.g., V4, is γ. For the forward and shorted configurations, respectively:

number

number

[0068] The following set of equations describes the current flowing in the forward direction:

number

Number

[0069] Here, V2 - V3 represents the measured value to be taken, and (Z5I5 - Z4I4) represents the error term. The following equation is used.

Number

Number

Number

[0070] Due to the relationships I5 = I9 and I4 = I8,

Number

[0071] As described above, the standard (e.g., forward / reverse) current operation may be indicated by a subscript of N in measurement terms. Under the condition of I6 >> I9, the relationship simplifies as follows.

Number

[0072] For the short - circuit mode in which current is supplied to both the source electrode 112 and the sink electrode 116 simultaneously, I6 + I9 = I2, which is approximately equal to I8 and which is also approximately equal to I9. However, due to the relationships Z2 << Z4 and Z2 << Z5, Z2I2 can be set to zero. This assumption simplifies the relationship as follows.

Number

[0073] Substitute the following equation.

Number

[0074] The results are:

number

[0075] The ratio of the voltages (e.g., V4 / V5) is fairly consistent and independent of the mode of operation. This has been verified empirically. In some variations, an additional measurement on V5 may be used to obviate the need for this approximation. The following relationship is used:

number

number

number

[0076] This can be simplified.

number

[0077] Consider the following:

number

number

number

[0078] If we subtract the number 25 from the number 15, we get:

number

Number

[0079] Finally, solving for the tissue impedance (Z2) gives the following result.

Number

[0080] Therefore, measuring all terms in the above equation provides the calibrated tissue impedance of the subject's tissue.

[0081] Using the above equation in Equation 28, the following results can be obtained.

Number

[0082] The previous analysis assumed I6 >> I9 under standard operation, and thus the term Z2I9 in Equation 14 can be set to zero. In a situation where current is supplied to both current paths (e.g., a short - circuit configuration), I6 + I9 = I2, which is approximately the same as I8 and I9. Also, if Z2 << Z4 and Z2 << Z5, then Z2I2 = Z2(I6 + I9) can be set to zero in Equation 11. Finally, the ratio of voltage V2 to voltage V5 can be the same in both the standard and short - circuit modes, and thus the ratio of V 4,N / V 4,B is approximately equal to the ratio of V 5,N / V 5,B

[0083] ​When a feature or element is referred to herein as being "on" another feature or element, it may be directly on the other feature or element, or there may be intervening features and / or elements present. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements present. Also, when a feature or element is referred to as being "connected," "attached," or "coupled" to another feature or element, it will be understood that it may be directly connected, attached, or coupled to the other feature or element, or that intervening features or elements may be present. In contrast, when a feature or element is referred to as being "directly connected," "directly attached," or "directly coupled" to another feature or element, there are no intervening features or elements present. Although described and represented with respect to one embodiment, the features and elements so described and represented may apply to other embodiments. Additionally, one skilled in the art will understand that a reference to a structure or feature being located "adjacent" another feature may have portions that overlap or underlie the adjacent feature.

[0084] The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting of the present invention. For example, as used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise. It will be further understood that the terms "comprises" and / or "comprising," when used herein, specify the presence of stated features, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ."

[0085] Spatially relative terms such as "below," "lower," "lower side," "upper," and "upper" are used herein for ease of description to describe the relationship of one element or feature to another element(s) or feature(s) as shown in the figures. It will be understood that spatially relative terms are intended to encompass various orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures were inverted, an element described as "below" or "below" another element or feature would be oriented "above" that other element or feature. Thus, the exemplary term "below" can encompass both an orientation of above and below. A device may be oriented differently (rotated 90 degrees or in another orientation), and the spatially relative descriptors used herein will be interpreted accordingly. Similarly, the terms "upward," "downward," "vertical," "horizontal," and the like are used herein for descriptive purposes only, unless specifically indicated otherwise.

[0086] Although the terms "first" and "second" may be used herein to describe various features / elements (including steps), these features / elements should not be limited by these terms unless the context indicates otherwise. These terms may be used to distinguish one feature / element from another. Thus, a first feature / element described below may be referred to as a second feature / element, and similarly, a second feature / element described below may be referred to as a first feature / element without departing from the disclosure of the present invention.

[0087] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" mean that various elements may be used jointly in methods and articles (e.g., compositions and apparatuses, including devices and methods). For example, the term "comprising" will be understood to imply the inclusion of any stated element or step, but not the exclusion of any other element or step.

[0088] As used herein in the specification and claims, including those used in the examples, unless otherwise expressly stated, all numbers may be read as if preceded by the word "about" or "approximately," even if the term does not explicitly appear. The terms "about" or "approximately," when used to describe a size and / or location, may indicate that the stated value and / or location is within a reasonable expected range for the value and / or location. For example, numerical values ​​may include ±0.1% of the stated value (or range of values), ±1% of the stated value (or range of values), ±2% of the stated value (or range of values), ±5% of the stated value (or range of values), ±10% of the stated value (or range of values), etc. Any numerical value given herein should also be understood to include values ​​about or approximately that value, unless the context indicates otherwise. For example, if the value "10" is disclosed, "about 10" is also disclosed. Any numerical range described herein is intended to include all subranges subsumed therein. Furthermore, when a value is disclosed, it is understood that "less than or equal to" that value, "greater than or equal to" that value, and possible ranges between the values ​​are also disclosed, as would be appropriately understood by one of ordinary skill in the art. For example, if a value "X" is disclosed, "less than or equal to X" and "greater than or equal to X" (e.g., where X is a numeric value) are also disclosed. It is further understood that throughout the application, data is provided in many different formats, and that this data represents endpoints and starting points and spans ranges for any combination of the data points. For example, if a specific data point "10" and a specific data point "15" are disclosed, it is understood that greater than 10, greater than or equal to 10, less than 15, less than or equal to 15, 10, or equal to 15 are also disclosed, as are values ​​between 10 and 15. It is also understood that each unit between two specified units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0089] While various exemplary embodiments are described above, any of numerous modifications may be made to the various embodiments without departing from the scope of the invention as set forth in the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative embodiments, one or more method steps may be skipped entirely. Optional features of various device and system embodiments may be included in some embodiments and not included in other embodiments. Accordingly, the foregoing description has been provided primarily for illustrative purposes and should not be construed as limiting the scope of the invention as it is set forth in the claims.

[0090] The examples and descriptions contained herein are illustrative, not limiting, and represent specific embodiments in which the subject matter may be practiced. As noted above, alternative embodiments may be utilized and derived therefrom, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein, individually or collectively, by the term "invention" merely for convenience, and are not intended to spontaneously limit the scope of this application to any single invention or inventive concept when more than one is actually disclosed. Thus, while specific embodiments have been shown and described herein, any configurations calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of the various embodiments. Combinations of the above embodiments, as well as other embodiments not specifically described herein, will be apparent to those skilled in the art upon reviewing the above description. [Explanation of symbols]

[0091] 100 Wearable Devices 104 Skin 106 Internal Electronic Components 112 first electrode, stimulation electrode 114 second electrode, sensing electrode 116 Third electrode, stimulation electrode 118 Fourth electrode, sensing electrode 200 Controller 202 Signal Generator 204 Signal Processor 206 Multiplexer 208 Power supply 210 Current Sensing Resistor

Claims

1. 1. A method of operating a controller for controlling a wearable device capable of monitoring a level of edema in a subject, the wearable device including a signal generator, at least two stimulation electrodes, and at least two sensing electrodes, the method comprising: the controller causes the signal generator to generate a first signal that causes a current to flow between the at least two stimulating electrodes and measures impedance between the at least two sensing electrodes at selected time intervals during a test period, thereby obtaining a plurality of impedance measurements; the controller fits the set of multiple impedance measurements to a Cole-Cole model to eliminate from the set of multiple impedance measurements any impedance measurement that exceeds a threshold from an expected value given by the Cole-Cole model, thereby obtaining a subset of impedance measurements that fit the Cole-Cole model; the controller converting each of the subset of impedance measurements into an edema index, thereby obtaining a plurality of edema indices; The method of operation wherein the controller generates from the plurality of edema indices a particular edema index that is the mean, mode or median of the plurality of edema indices for the test period.

2. the at least two stimulation electrodes include a source electrode and a sink electrode; the controller measures the impedance by supplying a first current between the source electrode and the sink electrode in a first direction and supplying a second current to the source electrode and the sink electrode simultaneously in the first direction and in a second direction opposite to the first direction, and measuring the impedance includes calculating the impedance based at least in part on a voltage between the at least two sensing electrodes when the first and second currents are supplied. The method of claim 1 .

3. Calculating the impedance may be performed by calculating the impedance as follows: a voltage difference between the at least two sensing electrodes when the first and second currents are applied, respectively; and a ratio of voltages at the first sensing electrode when the first and second currents are applied; and a current flowing through a current sensing resistor when the first current is supplied; The method of claim 2 , comprising determining the temperature based at least in part on:

4. A method according to any one of claims 1 to 3, wherein measuring the impedance is repeated between once every 10 minutes and once every 20 minutes.

5. A method according to any one of claims 1 to 4, wherein measuring the impedance is carried out for 1 to 4 seconds.

6. A method according to any one of claims 1 to 5, wherein the test period is between 1 hour and 24 hours in duration.

7. A method according to any one of claims 1 to 6, wherein the controller records the particular edema index.

8. The method of any one of claims 1 to 7, further comprising extending the test period to a predetermined period.

9. 9. The method of claim 8, wherein the extended period is between 1 month and 6 months.

10. The method of any one of claims 1 to 9, wherein the wearable device is configured to allow the at least two sensing electrodes to be placed on the subject's wrist.

11. 11. The method of claim 1, wherein the controller causes an alert to be output from at least one of the wearable device and the external device when the particular edema index exceeds or falls below a preselected value.

12. The method of claim 11 , wherein the controller comprises an interface circuit that causes the at least one of the wearable device and the external device to output the alert.

13. 13. A method according to claim 11 or 12, wherein the alert is an electronic report.

14. A method according to any one of claims 11 to 13, wherein the alert is an audible or visual report.

15. A method according to any preceding claim, wherein the subset of impedance measurements comprises at least 40% of the plurality of impedance measurements taken during the test period.

16. The method of any one of claims 1 to 15, wherein the wearable device is configured to allow the at least two sensing electrodes to be positioned at least 1 centimeter apart on the subject's skin.

17. 17. The method of claim 1, wherein the wearable device comprises a band including the at least two sensing electrodes and securable to the skin of the subject such that the at least two sensing electrodes are positioned at different points on the subject.

18. A controller for controlling a wearable device for monitoring a level of edema in a subject, the wearable device comprising at least two stimulating electrodes, at least two sensing electrodes, and a signal generator, the controller comprising: controlling the signal generator to generate a first signal that causes a current to flow between the at least two stimulation electrodes; measuring impedance between the at least two sensing electrodes at selected time intervals during a test period, thereby obtaining a plurality of impedance measurements; fitting the set of multiple impedance measurements to a Cole-Cole model to eliminate from the set of multiple impedance measurements those impedance measurements that exceed a threshold from an expected value given by the Cole-Cole model, thereby obtaining a subset of impedance measurements that fit the Cole-Cole model; converting each of the subset of impedance measurements into an edema index, thereby obtaining a plurality of edema indices; generating a specific edema index from the plurality of edema indices, the specific edema index being the mean, mode, or median of the plurality of edema indices for the test period; The controller is configured as follows:

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