(12) United States Patent
`Mastrototaro et al.
`
`I 1111111111111111 11111 lllll lllll lllll 111111111111111 111111111111111 11111111
`US00642484 7Bl
`US 6,424,847 Bl
`Jul. 23, 2002
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) GLUCOSE MONITOR CALIBRATION
`METHODS
`
`(75)
`
`Inventors: John J. Mastrototaro, Los Angeles;
`Todd M. Gross, Saugus; John J. Shin,
`Glendale, all of CA (US)
`
`(73) Assignee: Medtronic Minimed, Inc., Northridge,
`CA(US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`(21) Appl. No.: 09/511,580
`
`(22) Filed:
`
`Feb.23,2000
`
`Related U.S. Application Data
`( 60) Provisional application No. 60/121,584, filed on Feb. 25,
`1999.
`
`(51)
`
`Int. Cl.7 .................................................. A61B 5/00
`
`(52) U.S. Cl. ........................ 600/316; 600/365; 600/322
`(58) Field of Search ................................. 600/300-301,
`600/309-310, 316, 322-324, 345, 347,
`364-365, 331; 604/504; 436/14; 128/903-904
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`4,786,394 A * 11/1988 Enzer et al.
`................ 204/401
`5,068,536 A * 11/1991 Rosenthal ................... 250/341
`5,108,819 A
`4/1992 Heller et al. ................ 428/195
`5,391,250 A
`2/1995 Cheney, II et al.
`......... 156/268
`5,497,772 A * 3/1996 Schulman et al.
`.......... 600/317
`5,507,288 A * 4/1996 Bocker et al.
`.............. 600/322
`5,777,060 A
`7/1998 Van Antwerp ............... 528/28
`5,786,439 A
`7/1998 Van Antwerp et al.
`....... 528/77
`5,813,403 A * 9/1998 Soller et al. ................ 600/310
`5,830,133 A * 11/1998 Osten et al.
`................ 600/322
`5,885,211 A * 3/1999 Eppstein et al. ............ 600/309
`5,965,380 A
`10/1999 Heller et al. .................. 435/14
`6,049,727 A * 4/2000 Crothall ...................... 600/310
`6,088,608 A * 7/2000 Schulman et al.
`.......... 600/345
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`WO
`WO
`
`9856293
`9945375
`9945387
`9956613
`
`12/1998
`9/1999
`9/1999
`11/1999
`
`OTHER PUBLICATIONS
`
`Reach, G. et al., "A Method for Evaluating in vivo the
`Functional Characteristics of Glucose Sensors", Biosensors
`2 (Elsevier Applied Science Publishers Ltd., England-
`1986), pp. 211-220.
`Koudelka, M. et al., "Planar Amperometric Enzyme-Based
`Glucose Microelectode", Sensors and Actuators, 18
`(Elsevier Sequoia, The Netherlands-1989), pp. 157-165.
`Gernet, S. et al., "A Planar Glucose Enzyme Electrode",
`Sensors and Actuators, 17 (Elsevier Sequoia, The Nether(cid:173)
`lands-1989), pp. 537-540.
`
`(List continued on next page.)
`
`Primary Examiner-Eric F. Winakur
`Assistant Examiner-Matthew Kremer
`(74) Attorney, Agent, or Firm-Medtronic Minimed, Inc.
`ABSTRACT
`
`(57)
`
`A method of calibrating glucose monitor data includes
`collecting the glucose monitor data over a period of time at
`predetermined intervals. It also includes obtaining at least
`two reference glucose values from a reference source that
`temporally correspond with the glucose monitor data
`obtained at the predetermined intervals. Also included is
`calculating the calibration characteristics using the reference
`glucose values and the corresponding glucose monitor data
`to regress the obtained glucose monitor data. And calibrating
`the obtained glucose monitor data using the calibration
`characteristics is included. In preferred embodiments, the
`reference source is a blood glucose meter, and the at least
`two reference glucose values are obtained from blood tests.
`In additional embodiments, the calculation of the calibration
`characteristics is obtained using linear regression and in
`particular embodiments, least squares linear regression.
`Alternatively, the calculation of the calibration characteris(cid:173)
`tics is obtained using non-linear regression.
`
`51 Claims, 10 Drawing Sheets
`
`Page 1 of 25
`
`

`

`US 6,424,847 Bl
`Page 2
`
`OIBER PUBLICATIONS
`
`Velho, G. et al., "Strategies for calibrating a subcutaneous
`glucose sensor", Biomed. Biochim. Acta 48 (1989), pp.
`957-964.
`Koudelka, M. et al., "In-vivo Behaviour of Hypodermically
`Implanted Microfabricated Glucose Sensors" Biosensors &
`Bioelectronics 6
`(Elsevier Science Publishers Ltd.,
`England-1991), pp. 31-36.
`
`Mastrototaro, John J. et al., "An electroenzymatic glucose
`sensor fabricated on a flexible substrate", Sensors and
`Actuators B. 5 (Elsevier Sequoia-1991), pp. 139-144.
`Rebrin, Kerstin et al., "Subcutaneous glucose predicts
`plasma glucose independent of insulin: implications for
`continuous monitoring", The American Physiological Soci(cid:173)
`ety (1999), pp. E561-E571.
`* cited by examiner
`
`Page 2 of 25
`
`

`

`U.S. Patent
`
`Jul. 23, 2002
`Jul. 23, 2002
`
`US 6,424,847 Bl
`US 6,424,847 BI
`
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`Page 3 of 25
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`U.S. Patent
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`Page 7 of 25
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`

`

`U.S. Patent
`U.S. Patent
`
`Jul. 23, 2002
`Jul. 23, 2002
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`Jul. 23, 2002
`Jul. 23, 2002
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`

`

`U.S. Patent
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`Jul. 23, 2002
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`Sheet 8 of 10
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`
`

`

`U.S. Patent
`U.S. Patent
`
`Jul. 23, 2002
`Jul. 23, 2002
`
`Sheet 9 of 10
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`Page 11 of 25
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`

`

`U.S. Patent
`
`Jul. 23, 2002
`
`Sheet 10 of 10
`
`US 6,424,847 Bl
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`2 OR MORf PAIRrn CAUBRATION
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`Page 12 of 25
`
`

`

`US 6,424,847 Bl
`
`1
`GLUCOSE MONITOR CALIBRATION
`METHODS
`
`RELATED APPLICATIONS
`
`This application claims priority on U.S. Provisional
`Application Serial No. 60/121,584, filed Feb. 25, 1999 and
`entitled "Glucose Monitor Calibration Techniques Using
`Linear Regression", which is herein incorporated by refer(cid:173)
`ence in its entirety.
`
`FIELD OF THE INVENTION
`
`This invention relates to glucose monitor systems and, in
`particular embodiments, to calibration methods for glucose
`monitoring systems.
`
`BACKGROUND OF THE INVENTION
`
`45
`
`2
`glucose monitor data to regress the obtained glucose monitor
`data is included. And calibrating the obtained glucose moni(cid:173)
`tor data using the calibration characteristics is included. In
`preferred embodiments, the reference source is a blood
`5 glucose meter, and the at least two reference glucose values
`are obtained from blood tests. In additional embodiments,
`the calculation of the calibration characteristics is obtained
`using linear regression, and in particular embodiments,
`using least squares linear regression. Alternatively, the cal-
`10 culation of the calibration characteristics is obtained using
`non-linear regression or a non-regression technique.
`In particular embodiments, the predetermined period of
`time is a 24 hour period, and the predetermined intervals are
`5 minute intervals. Further embodiments may include the
`15 step of shifting the data by a predetermined time factor, such
`as for example, ten minutes. Preferably, the calibration is
`performed while obtaining glucose monitor data. However,
`alternative embodiments may perform the calibration on
`glucose monitor data that has been collected for post pro-
`20 cessing by another processing device.
`According to an embodiment of the invention, a method
`of calibrating glucose monitor data includes obtaining glu(cid:173)
`cose monitor data at a predetermined memory storage rate.
`Also included is obtaining at least one blood glucose refer(cid:173)
`ence reading from a blood glucose measuring device that
`corresponds with at least one glucose monitor data point
`obtained at the predetermined memory storage rate. Calcu(cid:173)
`lating a calibration factor using the at least one blood
`glucose reference reading and the corresponding at least one
`glucose monitor data point is included. And calibrating the
`obtained glucose monitor data using the calibration factor is
`included. In preferred embodiments, after a first calibration
`factor is calculated, at least one previous calibration factor
`is used with at least one blood glucose reference reading
`35 from a blood glucose measuring device and its at least one
`corresponding glucose monitor data point to calculate a
`calibration factor. In additional embodiments, at least two
`blood glucose reference readings are used for calibration. In
`further embodiments, the calculation of the calibration fac-
`40 tor is obtained using linear regression, and in particular least
`squares linear regression. Alternatively, calculation of the
`calibration factor uses non-linear regression or a non(cid:173)
`regression technique.
`In particular embodiments, the calibration factor is
`applied to glucose monitor data obtained before a last blood
`glucose reference reading from a blood glucose measuring
`device that corresponds with at least one glucose monitor
`data point obtained at a predetermined memory storage rate
`is used to calculate the calibration factor. Alternatively, the
`calibration factor is applied to glucose monitor data obtained
`after the last blood glucose reference reading from a blood
`glucose measuring device that is used to calculate the
`calibration factor.
`In particular embodiments, the predetermined memory
`storage rate is once every 5 minutes. And the glucose
`monitor data that is obtained at a predetermined memory
`storage rate is the result of utilizing at least 2 sample values
`sampled from a glucose sensor at a rate faster than the
`60 memory storage rate.
`In preferred embodiments, at least one blood glucose
`reference reading from a blood glucose measuring device is
`obtained during a predetermined calibration period, and a
`calibration factor is calculated using those readings after
`65 every predetermined calibration period. In particular
`embodiments, the predetermined calibration period is 24
`hours. In further preferred embodiments, a predetermined
`
`Over the years, body characteristics have been determined
`by obtaining a sample of bodily fluid. For example, diabetics
`often test for blood glucose levels. Traditional blood glucose
`determinations have utilized a painful finger prick using a
`lancet to withdraw a small blood sample. This results in
`discomfort from the lancet as it contacts nerves in the
`subcutaneous tissue. The pain of lancing and the cumulative
`discomfort from multiple needle pricks is a strong reason 25
`why patients fail to comply with a medical testing regimen
`used to determine a change in a body characteristic over a
`period of time. Although non-invasive systems have been
`proposed, or are in development, none to date have been
`commercialized that are effective and provide accurate 30
`results. In addition, all of these systems are designed to
`provide data at discrete points and do not provide continuous
`data to show the variations in the characteristic between
`testing times.
`A variety of implantable electrochemical sensors have
`been developed for detecting and/or quantifying specific
`agents or compositions in a patient's blood. For instance,
`glucose sensors are being 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 treat(cid:173)
`ment regimen which typically includes the regular admin(cid:173)
`istration of insulin to the patient. Thus, blood glucose
`readings improve medical therapies with semi-automated
`medication infusion pumps of the external type, as generally
`described in U.S. Pat. Nos. 4,562,751; 4,678,408; and 4,685,
`903; or automated implantable medication infusion pumps,
`as generally described in U.S. Pat. No. 4,573,994, which are
`herein incorporated by reference. Typical thin film sensors
`are described in commonly assigned U.S. Pat. Nos. 5,390,
`671; 5,391,250; 5,482,473; and 5,586,553 which are incor(cid:173)
`porated by reference herein. See also U.S. Pat. No. 5,299,
`571.
`
`50
`
`55
`
`SUMMARY OF THE DISCLOSURE
`
`It is an object of an embodiment of the present invention
`to provide an improved glucose monitor system and method,
`which obviates for practical purposes, the above mentioned
`limitations.
`According to an embodiment of the invention, a method
`of calibrating glucose monitor data includes obtaining glu(cid:173)
`cose monitor data at predetermined intervals over a period of
`time. It also includes obtaining at least two reference glucose
`values from a reference source that correspond with the
`glucose monitor data obtained at the predetermined inter(cid:173)
`vals. Additionally, calculating calibration characteristics
`using the at least two reference values and the corresponding
`
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`US 6,424,847 Bl
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`4
`ing glucose monitor data. It also includes means for obtain(cid:173)
`ing from another blood glucose measuring device at least
`one blood glucose reference reading that is temporally
`associated with at least one glucose monitor data reading.
`Means for calculating a calibration equation using the at
`least one blood glucose reference reading and the corre(cid:173)
`sponding at least one glucose monitor data reading is
`included. And means for calibrating the glucose monitor
`data using the calibration equation is also included.
`Other features and advantages of the invention will
`become apparent from the following detailed description,
`taken in conjunction with the accompanying drawings which
`illustrate, by way of example, various features of embodi(cid:173)
`ments of the invention.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`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
`several figures.
`FIG. 1 is a is a perspective view illustrating a subcuta(cid:173)
`neous glucose sensor insertion set and glucose monitor
`device in accordance with an embodiment of the present
`invention;
`FIG. 2 is a cross-sectional view of the sensor set and
`glucose monitor device as shown along the line 2-2 of FIG.
`1;
`
`15
`
`20
`
`3
`time shift is used to temporally correlate the at least one
`blood glucose reference reading from a blood glucose mea(cid:173)
`suring device with the at least one glucose monitor data
`point obtained at the predetermined memory storage rate. In
`particular embodiments, the predetermined time shift is ten 5
`minutes.
`In particular embodiments, one or more calculations for
`calculating a first calibration factor is different from the one
`or more calculations for calculating subsequent calibration
`factors. In other particular embodiments, the calculation for 10
`calculating a first calibration factor uses a single-point
`calibration equation. In further particular embodiments, the
`single-point calibration equation includes an offset value. In
`other particular embodiments, the one or more calculations
`for calculating a calibration factor other than the first cali-
`bration factor uses a linear regression calibration equation,
`a non-linear regression calibration equation, or a non(cid:173)
`regression technique.
`According to an embodiment of the invention, a method
`of calibrating glucose monitor data includes obtaining glu-
`case monitor data. It also includes obtaining from another
`blood glucose measuring device at least one blood glucose
`reference reading that is temporally associated with at least
`one glucose monitor data reading. Determining a calibration
`equation using the at least one blood glucose reference 25
`reading and the corresponding at least one glucose monitor
`data reading is also included. And calibrating the glucose
`monitor data using the calibration equation is included.
`According to another embodiment of the invention, a
`method of calibrating body characteristic monitor data
`includes obtaining body characteristic monitor data. It also
`includes obtaining from another characteristic measuring
`device at least one characteristic reference reading that is
`temporally associated with at least one characteristic moni(cid:173)
`tor data point.
`Calculating calibration characteristics using the at least
`one characteristic reference reading and the corresponding at
`least one characteristic monitor data point is included. And
`calibrating the obtained characteristic monitor data using the
`calibration characteristics is included. In particular 40
`embodiments, at least two body characteristic reference
`readings are used for calculating the calibration character(cid:173)
`istics. In particular embodiments, the calculation for calcu(cid:173)
`lating the calibration characteristics is a linear regression
`calculation.
`According to additional embodiments of the invention, an
`apparatus for calibrating glucose monitor data includes a
`glucose monitor, glucose sensor, a blood glucose meter and
`a processor. The glucose monitor includes a glucose monitor
`memory for storing glucose monitor data. The glucose
`sensor is electronically coupled to the glucose monitor to
`supply the glucose monitor data. The blood glucose mea(cid:173)
`suring device provides at least one blood glucose reference
`reading that is temporally associated with at least one
`glucose monitor data point. And the processor includes 55
`software to calculate calibration characteristics using the at
`least one blood glucose reference reading that is temporally
`associated with at least one glucose monitor data point, and
`the processor applies the calibration characteristics to the
`glucose monitor data. In particular embodiments, the at least 60
`one blood glucose reading is entered into the glucose
`monitor. In particular embodiments, the glucose monitor
`includes the processor, or alternatively, the processor is in a
`separate device that receives glucose monitor data from the
`glucose monitor.
`In other embodiments of the invention, an apparatus for
`calibrating glucose monitor data includes means for obtain-
`
`FIG. 3 is a cross-sectional view of a slotted insertion
`30 needle used in the insertion set of FIGS. 1 and 2;
`FIG. 4 is a cross-sectional view as shown along line 4--4
`of FIG. 3;
`FIG. 5 is a cross-sectional view as shown along line 5-5
`35 of FIG. 3;
`FIG. 6 is a partial cross-sectional view corresponding
`generally with the encircled region 6 of FIG. 2;
`FIG. 7 is a cross-sectional view as shown along line 7-7
`of FIG. 2.
`FIGS. 8(a-c) are diagrams showing a relationship
`between sampled values, interval values and memory stor(cid:173)
`age values.
`FIG. 9 is a chart showing clipping limits.
`FIG. 10 is a sample computer screen image of a post
`processor analysis of glucose monitor data.
`FIG. 11 is a chart illustrating the pairing of a blood
`glucose reference reading with glucose monitor data.
`FIG. 12 is a chart illustrating an example of a single-point
`50 calibration.
`FIG. 13 is a block diagram of a single-point calibration
`technique.
`FIG. 14 is a chart illustrating an example of a linear
`regression calibration.
`FIG. 15 is a block diagram of a linear regression calibra(cid:173)
`tion technique.
`
`45
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`
`As shown in the drawings for purposes of illustration, the
`invention is embodied in calibration methods for a glucose
`monitor that is coupled to a sensor set to provide continuous
`data recording of readings of glucose levels from a sensor
`65 for a period of time. In preferred embodiments of the present
`invention, the sensor and monitor are a glucose sensor and
`a glucose monitor for determining glucose levels in the
`
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`US 6,424,847 Bl
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`5
`
`5
`blood and/or bodily fluids of a user. However, it will be
`recognized that further embodiments of the invention may
`be used to determine the levels of other body characteristics
`including analytes or agents, compounds or compositions,
`such as hormones, cholesterol, medications concentrations,
`viral loads ( e.g., HIV), bacterial levels, or the like. The
`glucose sensor is primarily adapted for use in subcutaneous
`human tissue. However, in still further embodiments, one or
`more sensors may be placed in other tissue types, such as
`muscle, lymph, organ tissue, veins, arteries or the like, and 10
`used in animal tissue to measure body characteristics .
`Embodiments may record readings from the sensor on an
`intermittent, periodic, on-demand, continuous, or analog
`basis. FIGS. 1-7 illustrate a glucose monitor system 1 for
`use with the calibration methods. The glucose monitor
`system 1, in accordance with a preferred embodiments of the
`present invention, includes a subcutaneous glucose sensor
`set 10 and a glucose monitor 100. In preferred embodiments,
`the glucose monitor 100 is of the type described in U.S.
`patent. application Ser. No. 60/121,664, filed on Feb. 25,
`1999, entitled "Glucose Monitor System", which is herein
`incorporated by reference. In alternative embodiments, the
`glucose monitor is of the type described in U.S. patent
`application Ser. No. 09/377,472, filed Aug. 19, 1999,
`entitled "Telemetered Characteristic Monitor System And
`Method Of Using The Same", which is incorporated by
`reference herein.
`Preferably, the glucose monitor 100 is worn by the user
`and is connected to a surface mounted glucose sensor set 10
`that is attached to a user's body by an electrically conductive
`cable 102, of the type described in U.S. patent application
`Ser. No. 60/121,656, filed on Feb. 25, 1999, entitled "Test
`Plug and Cable for a Glucose Monitor", which is incorpo(cid:173)
`rated by reference herein. In preferred embodiments, the
`sensor interface may be configured in the form of a jack to
`accept different types of cables that provide adaptability of
`the glucose monitor 100 to work with different types of
`subcutaneous glucose sensors and/or glucose sensors placed
`in different locations of the user's body. However, in alter(cid:173)
`native embodiments, the sensor interface is permanently
`connected to the cable 102. In additional alternative
`embodiments, a characteristic monitor is connected to one or
`more sensor sets to record data of one or more body
`characteristics from one or more locations on or in the user's
`body.
`The glucose sensor set 10 is of the type described in U.S.
`patent application Ser. No. 60/121,655, filed on Feb. 25,
`1999, entitled "Glucose Sensor Set", or U.S. Pat. Ser. No.
`08/871,831, filed on Jun. 9, 1997, entitled "Insertion Set For
`A Transcutaneous Sensor", which are incorporated by ref(cid:173)
`erence herein. The glucose sensor 12, of the type described
`in U.S. patent application Ser. No. 29/101,218, filed on Feb.
`25, 1999, entitled "Glucose Sensor", or described in com(cid:173)
`monly assigned U.S. Pat. Nos. 5,390,671; 5,391,250; 5,482,
`473; and 5,586,553 which are incorporated by reference
`herein; extends from the glucose sensor set 10 into the user's
`body with electrodes 20 of the glucose sensor 12 terminating
`in the user's subcutaneous tissue. See also U.S. Pat. No.
`5,299,571. However, in alternative embodiments, the glu(cid:173)
`cose sensor 12 may use other types of sensors, such as
`chemical based, optical based, or the like. In further alter(cid:173)
`native embodiments, the sensors may be of a type that is
`used on the external surface of the skin or placed below the
`skin layer of the user for detecting body characteristics.
`The glucose monitor 100 generally includes the capability
`to record and store data as it is received from the glucose
`sensor 12, and includes either a data port (not shown) or
`
`6
`wireless transmitter and/or receiver ( also not shown) for
`transferring data to and/or from a data processor 200 such as
`a computer, communication station, a dedicated processor
`designed specifically to work with the glucose monitor, or
`the like. The glucose monitor is generally of the type
`described in U.S. patent application Ser. No. 09/377,472,
`filed Aug. 19, 1999, entitled "Telemetered Characteristic
`Monitor System And Method of Using The Same", which is
`incorporated by reference herein.
`Preferably, the glucose monitor system 1 minimizes
`inconvenience by separating complicated monitoring pro(cid:173)
`cess electronics into two separate devices; the glucose
`monitor 100, which attaches to the glucose sensor set 10;
`and the data processor 200, which contains the software and
`15 programming instructions to download and evaluate data
`recorded by the glucose monitor 100. In addition, the use of
`multiple components (e.g., glucose monitor 100 and data
`processor 200) facilitates upgrades or replacements, since
`one module, or the other, can be modified, re-programmed,
`20 or replaced without requiring complete replacement of the
`monitor system 1. Further, the use of multiple components
`can improve the economics of manufacturing, since some
`components may require replacement on a more frequent
`basis, sizing requirements may be different for each module,
`25 different assembly environment requirements, and modifi(cid:173)
`cations can be made without affecting the other components.
`The glucose monitor 100 takes raw glucose sensor data
`from the glucose sensor 12 and assesses it during real-time
`and/or stores it for later processing or downloading to the
`30 data processor 200, which in turn analyzes, displays, and
`logs the received data. The data processor 200 utilizes the
`recorded data from the glucose monitor 100 to analyze and
`review the blood glucose history. In particular embodiments,
`the glucose monitor 100 is placed into a com-station which
`35 facilitates downloading data to a personal computer for
`presentation to a physician. A software is used to download
`the data, create a data file, calibrate the data, and display the
`data in various formats including charts, forms, reports,
`graphs, tables, lists, and the like. In further embodiments, the
`40 glucose monitor system 1 may be used in a hospital envi(cid:173)
`ronment or the like.
`In alternative embodiments, the glucose monitor includes
`at least portions of the software described as contained
`within the data processor 200 above. The glucose monitor
`45 might contain the necessary software to calibrate glucose
`sensor signals, display a real-time blood glucose value, show
`blood glucose trends, activate alarms and the like. A glucose
`monitor with these added capabilities is useful for patients
`that might benefit from real-time observations of their blood
`50 glucose characteristics even while they're not in close
`proximity to a computer, communication device or dedi(cid:173)
`cated independent data processor.
`As shown in FIG. 2, the data processor 200, may include
`a display 214 that is used to display the calculated results of
`55 the raw glucose sensor data received via a download from
`the glucose monitor 100. The results and information dis(cid:173)
`played includes, but is not limited to, trending information
`of the characteristic ( e.g., rate of change of glucose), graphs
`of historical data, average characteristic levels (e.g.,
`60 glucos