This application claims priority to provisional application, U.S. Application No. 62/045,328, filed September 3, 2014, the disclosure of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention is generally in the field of transdermal analyte monitoring systems and methods of using thereof.

BACKGROUND OF THE INVENTION

An aging population and the increasing need for management of chronic conditions is leading to a large population needing monitoring and support. This will be increasingly performed through primary healthcare, pharmacies and in a home setting. Transdermal analyte monitoring systems (TAMS) offer simple and non-invasive monitoring of a variety of chemical and bio-chemical species, such as glucose. Transdermal analyte monitoring systems are also finding applications in other areas. Recent reports by the U.S. Department of Transportation have highlighted the increased use of continuous transdermal alcohol monitoring for ensuring abstinence from alcohol for repeat DWI offenders (McKnight et ah, Transdermal alcohol monitoring: Case studies. (Report No. DOT HS 811 603). Washington, DC: National Highway Traffic Safety Administration (2012)).

Analytical biosensors can be used to manage diabetes. The biosensors are small and convenient, and sample tiny amounts of fluids that lie just below the skin, making measuring glucose levels pain- free and noninvasive. Such devices combine the advantages of electrochemical signal transduction with the specificity inherent in biological interactions.

Despite recent improvements in biosensor based TAMS, the available systems suffer from several disadvantages. A biosensor system typically contains only one working terminal and at least one reference terminal, which are used to measure a signal associated with a concentration of the analyte in the patient. The output signal, typically a raw data stream, also includes non-analyte signals due to background interferences, such as noise due to mechanical, biochemical, and/or chemical factors. These

interferences cause inaccuracies in analyte sensing. Hydrogel sensors typically have short shelf lives, while bacterial growth or growth of other microorganism can contaminate or foul many biosensors. Some TAMS require pretreatment of the site with a hydrating formulation prior to applying the sensor assembly. These interferences cause inaccuracies in analyte sensing. In glucose sensing, these inaccuracies can cause a patient to think his/her blood glucose level is fine when it is really too high or too low. The results obtained from such devices may also cause a patient to administer a higher or lower level of insulin than needed.

Most TAMS, especially those based upon biosensors such as enzymatic electrochemical cells, have limited time of use, ranging from 12 hours up to about 48 hours per use. This time of use is further limited by background signals and noise during the first few hours of use associated with powering on the sensors and placing the sensors on the skin. There may be several background noises associated with equilibration of the sensor and background current variations due to variations in the surface. Many sensors, when powered on, will exhibit background noise related to the decay of the Poise potential and the equilibration of the sensor electrodes. These interferences lead to inaccuracies in measuring analyte concentrations during the first few hours of use, i.e. until the background signals associated with these interferences have decayed or otherwise reached a steady state. There exists a need for TAMS that more accurately measure analyte concentrations over a greater portion of the time of use, including when the TAMS is initially placed on the skin.

It is therefore an object of the invention to provide improved TAMS that can accurately monitor analyte concentrations over a greater portion of the time of use.

It is a further object of the invention to provide TAMS that can accurately measure analyte concentration during the initial and/or early time of use, or shortly after the TAMS is placed on the skin. It is an additional object of the invention to provide these TAMS with improved accuracy, especially during early-time detection, for measuring analyte concentrations.

It is also an object of the invention to provide methods of using

TAMS to provide more accurate analyte detection for a longer period of time.

SUMMARY OF THE INVENTION

In some embodiments a transdermal analyte monitoring system is provided containing a computer readable storage medium having stored thereon a computer program containing instructions for computing one or more analyte concentrations. In other embodiments a computer readable storage medium for use with a transdermal analyte monitoring system is provided having stored thereon a computer program for computing one or more analyte concentrations.

Methods of using the computer readable storage media in a

transdermal analyte monitoring system are provided. Methods of using the transdermal analyte monitoring systems are also provided. In preferred embodiments the analyte is glucose.

The computer program contains a set of instructions for computing one or more offset corrections. The offset corrections correct for one or more sources of noise and/or error in a transdermal analyte monitoring system.

The computer program contains a set of instructions for computing one or more analyte concentrations using one or more offset corrections. The offset corrections provided reduce the error associated with computing the

concentration of one or more analytes.

The computer program provided may contain a set of instructions for computing a break-in offset. The break-in offset correction can be computed according to the double-exponential formula:

S _BreakIn (t) = S _EXT {x ^■ _Eq . i where S _BreakIn (t ) is the break-in offset at time t, S _EXT is the value of the sensor data at some extremum, and t _EXT is the time when the extremum in the sensor data is achieved. In some embodiments, the sensor data is current and the break-in offset current correction provided is computed using the double exponential formula:

I _BreakIn (0 = I _MAX {x ^■ Eq. 2 where I _Breakln (t) is the break-in current at time t, I _MAX is the maximum break- in current, and t _MJX is the time when the maximum break-in current is achieved.

In Eq. 1 and 2, x is a real number between 0 and 1, and τ _χ and τ ₂ are decay time constants for the break-in offset.

The computer program may contain a set of instructions for computing an on-skin offset. The on-skin offset correction can be computed according to the formula:

^ OnSkin ⁽ 0 ⁼ ^MAG ^' f ^' E 3

{b + {l - b)exp[- t /c + {l - f)- {d + {l - d)exp[- t / e]} ^¾' where S _0nSkin (t) is the on-skin offset at time t, relative to a reference time, and S _MAG is the magnitude of the on-skin offset at the reference time. In some embodiments, the sensor data is current and the on-skin offset current correction is computed using the formula:

I OnSkin (0 ⁼ ^ MAG ' f ' £ ^

{b + (l - b)exp[- tlc]} + (\ - f)- {d + (\ - rf)exp[- tie]}

where I _0nSkin (t) is the on-skin offset current at time t, relative to a reference time, and I _MAG is the magnitude of the on-skin current at the reference time.

Eq. 3 and 4, b, c, d, e, and / are real numbers.

The computer program provided may contain a set of instructions for correcting one or more offsets to accommodate for changes in temperature. In some embodiments the instructions include multiplying the offset by a temperature-dependent function. The temperature dependent function can have the formula Core 1 ^~ * ^~ ^orc * (,Τ ^α οτο ) ^~ * ^{~ C} OTC * (,Τ ^α οτο ) ' Eq. 5 where C _0TC is the offset temperature correction at temperature, T, and a _0TC , b _0TC , and c _0TC are real numbers.

When the analyte concentration is directly proportional to the corrected sensor data, the instructions for computing an analyte

concentration can include using the formula:

[A] = Slope ^■ S _A + Intercept , Eq. 6 where [A] denotes the concentration of an analyte, A, the Slope is the dependence of the analyte concentration on the corrected sensor data, S _A , and the Intercept is the analyte concentration when the value of the sensor data is zero. The Slope can be corrected to compensate for changes in temperature. In some embodiments the instructions include correcting the Slope to compensate for changes in temperature using the formula

Slope _TC = Slope * (l + b _STC * (Τ - a _STC ) + c _STC * (Τ - a _STC f ), Eq. 7 where Slope _TC is the temperature-corrected slope, and a _STC , b _STC , and c _STC are real numbers.

The analyte can be a small molecule, protein, carbohydrate, nucleic acid, or lipid. In preferred embodiments, the analyte is glucose. In preferred embodiments the sensor data is current and the analyte is glucose. The program can include instructions for computing the glucose concentration using the formula:

[glu cos e] = Slope _TC - I _{G TC} , Eq. 8 where [glucose] is the glucose concentration, Slope _TC is the temperature- corrected slope, and I _{G TC} is the temperature-corrected glucose current. The temperature corrected glucose current is preferably corrected by subtracting a temperature corrected break-in current, a temperature corrected on-skin current, or both from the raw current data. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a flow diagram of an exemplary computer program for converting sensor data into an analyte concentration.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

The term "analyte", as used herein, denotes any physiological compound or fragment thereof of interest being detected and/or measured in a transdermal analyte monitoring system. The measurement of an analyte may involve a chemical, electrical, physical, enzymatic, or optical signal. A detectable signal (e.g., a chemical signal or electrochemical signal) can be obtained, either directly or indirectly, from such an analyte or derivatives thereof.

The terms "continuous monitoring" and "continuously monitoring" are used interchangeably herein and refer to the real-time or substantially real-time monitoring of an analyte in a continuous or substantially continuous manner, i.e. at the same time or at almost the same time as measurement, i.e. within about 1,000 ms, 100 ms, 10 ms, or 1 ms.

Monitoring in a continuous or substantially continuous manner refers to monitoring via discrete measurements closely spaced over time, for example at least 1, 10, 100, or 1,000 measurements per second throughout the time period of monitoring.

The term "transdermal analyte monitoring system" or "TAMS", as used herein, refers to a system for the noninvasive or minimally invasive detection or monitoring of one or more analytes across the skin or mucosal tissue. There are many TAMS designs known to the skilled artisan. It will be understood that the methods described herein can be applied as is or with only slight modification to these designs and to designs not yet envisioned. TAMS can involve the extraction or the micro-extraction of an analyte from beneath the tissue surface, from the blood, from the interstitial fluid, from the transcellular fluid, from the lymphatic fluid, or from sweat or perspiration.

This includes extraction of an analyte using iontophoresis (reverse iontophoresis), electroosmosis, sonophoresis (see, e.g., U.S. Patent No. 5,636,632), microdialysis, suction, and passive diffusion. The systems can include employing thermal poration, laser microporation, electroporation, micro fine lances, microfine canulas, subcutaneous implants or insertions. These systems can be coupled with application of skin penetration enhancers or skin permeability enhancing technique such as various substances or physical methods such as tape stripping or pricking with micro-needles.

The terms "biosensor" and "sensor" are used interchangeably herein to refer to any of several sensing elements known to those skilled in the art and capable of producing an output signal in response to the presence of or changes in the concentration of one or more analytes. Sensors can include electrochemical sensors, electrical voltage sensors, electrical current sensors, temperature sensors, flow rate sensors, pressure sensors, acoustic sensors, pH sensors, accelerometers, tachometers, and concentration sensors. Sensors can include galvonometers, potentiometers, potentiostats, bipotentiostats, polypotentiostats, enzyme catalysis based sensors, redox cella,

biofunctionalized ion-selective field effect transistors, and potentiometric biosensors.

The terms "calculating" and "computing" are used interchangeably herein and refer to forms of numeric and/or algebraic computations performed by one or more computing devices or processors.

The term "accurate", as used herein, refers to measuring an analyte concentration with a mean absolute relative difference (MARD) of not more than 20%, 17%, 15%, 13%, 10%, or 5% with respect to a reference analyte measurement. The reference analyte measurement is a measurement taken from a blood sample, e.g. from finger stick blood samples or from an IV line.

The term "sensor data", as used herein, refers to data not processed or analyzed by the transdermal analyte monitoring system, for example by a processor or computing device to compute an analyte concentration. Sensor data has not been corrected for one or more offset corrections as defined herein. Examples of sensor data may include the data or signal received from a sensor in a transdermal analyte monitoring system. Sensor data can be analog or digital, although digitized data is preferred. The term "sensor data" may be used to refer to data that has been corrected within a sensor to remove background noise or other similar corrected made by the sensor.

The term "corrected data", as used herein, refers to data corrected for one or more variations or sources of error by applying an offset correction as defined herein. The corrected data is obtained by adding or subtracting one or more values from the sensor data, multiplying or dividing the sensor data by a value, or some combination thereof. The term "corrected data" can refer exclusively to data having been corrected by one or more offset corrections described herein.

The term "operational lifetime", as used herein, refers to the time from the beginning of operation, i.e. when the sensor assembly is placed onto the skin site, until the sensor assembly is removed or replaced.

The term "correction", as used herein, refers to a numerical approximation to one or more sources of error that, when applied to the sensor data, may remove or approximately remove the source of error and/or that may improve the accuracy in measuring the anlyte concentration.

The term "additive correction", as used herein, refers to a correction applied to the sensor data by adding or subtracting the correction from the sensor data to obtain the corrected data.

The term "multiplicative correction", as used herein, refers to a correction applied to the sensor data by multiplying or dividing the sensor data by the correction to obtain the corrected data.

The term "derivative", as used herein, can refer to a functional derivative or to a derivative of a compound or chemical substance. The meaning will be understood by context.

The term "derivative" when referring to a derivative of a function refers to the functional first derivative with respect to time should such a derivative exist. The functional first derivative will exist if there is no removable discontinuity, infinite discontinuity, jump discontinuity, or vertical inflection point. The derivative may be an analytic derivative of the function. The derivative may be numerically estimated by two or more sensor datums. Methods of numerical differentiation are known in the art, and include central, forward, or backward finite difference methods, Newton's method, Crank-Nicolson method, or variations thereof.

The term "derivative", when referring to a derivative of a compound or chemical substance refers to any compound having the same or a similar core structure to the compound but having at least one structural difference, including substituting, deleting, and/or adding one or more atoms or functional groups. The term "derivative" does not mean that the derivative is synthesized from the parent compound either as a starting material or intermediate, although this may be the case. The term "derivative" can include salts, prodrugs, or metabolites of the parent compound.

The term "second derivative", as used herein, refers to the second derivative of a function with respect to time should such a derivative exist. The second derivative may be an analytic second derivative. The second derivative may be a numerical second derivative estimated by at least three sensor datums. Methods of numerical differentiation are known in the art, and can include central, forward, or backward finite difference methods, Newton's method, Crank-Nicolson method, or variations thereof.

The term "extremum", as used herein, refers to a local maximum or minimum of a function or of a set of data points. A function or collection of data may have more than one extremum, referred to collectively as

"extrema". The extremum of a function can be computed analytically by determining the point at which the first derivative of the function is zero. The extremum may be computed numerically by taking the most positive (maximum) or most negative (minimum) of the data points over a given period of time. The extremum may be computed numerically using finite difference methods or variations thereof.

II. Offset Corrections for Transdermal Analyte Monitoring

Offset corrections for a transdermal analyte monitoring system are provided. The offset corrections include corrections for break-in of the analyte monitoring system, corrections for a portion of the analyte monitoring system being placed on the skin, or a combination thereof. The offset corrections allow for early time and/or continuous time monitoring of one or more analytes or analyte concentrations when used with a transdermal analyte monitoring system. The offset corrections can be used with other analyte sensor corrections, data corrections, and/or noise reduction algorithms known in the art. In some embodiments the offset corrections are used without additional methods of sensor correction, data correction, and/or noise reduction.

The offset corrections can correct the sensor data prior to or at the time of computing the analyte concentration. In some embodiments the offset correction is a multiplicative correction. In preferred embodiments the offset correction is an additive correction. In some embodiments the corrected sensor data is computed using the formula:

A ⁼ ^sensor ^~ offset ' ¾. 9 where S _A is the analyte sensor data (the portion of the sensor data value due to the analyte, A), S _sensor is the raw or uncorrected sensor data, and S offset is the offset correction. In some embodiments offset is an offset correction corrected for changes in temperature. In some embodiments offset is ^a temperature-independent offset correction. $ offset can be the break-in offset, the on-skin offset, or the sum of both the break-in offset and the on-skin offset. $ offset ^ma y include contributions from additional corrections to the sensor data.

In some embodiments the sensor data is current and the analyte current is computed using the formula:

I A ⁼ I sensor ~ ^ offset Eq. 10 where I _A is the analyte current (the portion of the current due to the analyte, A), I _sensor is the raw or uncorrected current, and I offset is the offset current correction. In some embodiments I offset is an offset current correction corrected for changes in temperature. In some embodiments I offset is a temperature-independent offset current correction. I offset can be the break-in offset current, the on-skin offset current, or the sum of both the break-in offset current and the on-skin offset current. I offset ^ma y include

contributions from additional corrections to the sensor current data. In some embodiments the analyte is glucose and, I _A the analyte current, is the portion of the current due to glucose.

In some embodiments the offset corrections are applied to the sensor data such that the TAMS is able to accurately monitor of one or more analyte concentrations immediately upon placement on the skin. The offset corrections can allow for accurate measurement by the TAMS of one or more analyte concentrations within seconds or minutes of placing the system or a portion thereof onto the skin. In some embodiments accurate measurements can be obtained immediately, within 10 seconds, within 30 seconds, within 1 minute, within 5 minutes, within 10 minutes, or within 30 minutes of placement.

The offset correction may be an additive correction. Preferably the additive offset correction reduces the error associated with the early-time calculation of the analyte concentration. The additive offset correction can reduce the error associated with computing an analyte concentration during the first 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, or 180 minutes of operation of a TAMS at the skin site. In some embodiments the additive offset correction zeroes over time, i.e. after 30 minutes, after 60 minutes, after 90 minutes, after 120 minutes, after 150 minutes, or after 180 minutes. The additive offset correction can reduce the error associated with computing an analyte concentration by greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, or greater than 99% compared to when the correction is not applied.

The offset correction may be a multiplicative correction. Preferably the multiplicative offset correction reduces the error associated with the early -time calculation of the analyte concentration. The multiplicative offset correction can reduce the error associated with computing an analyte concentration during the first 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, or 180 minutes of operation of a TAMS at the skin site. The multiplicative offset correction may decay over time (goes to unity). The time period can be after 30 minutes, after 60 minutes, after 90 minutes, after 120 minutes, after 150 minutes, or after 180 minutes or application of the correction. The multiplicative offset correction can reduce the error associated with computing an analyte concentration by greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, or greater than 99% compared to when this offset correction is not applied.

A. Break-In Offset Correction

The break-in offset correction is a correction that reduces the error associated with the temporal profile of the sensor data after the transdermal analyte monitoring system is powered on. The break-in offset correction can depend upon time, temperature, or preferably both time and temperature. The break-in offset correction can be an additive correction or a multiplicative correction. The break-in offset correction is preferably an additive correction.

The break-in offset correction can be computed using a polynomial function, Nth root function, exponential function, hyperbolic function, logarithmic function, power function, trigonometric function, or a ratio, integral, or derivative thereof. The break-in offset can be computed using any combination of the above functions, ratios, integrals, or derivatives. In some embodiments the break-in offset correction is computed using Nth root functions, exponential functions, or a combination thereof. The break-in offset correction can be computed with a function having 2, 3, 4, 5, 6, or more terms. In a preferred set of embodiments the break-in offset correction is computed using a combination of two or more exponential functions. The break-in offset correction can be computed according to the double- exponential formula: where S _Breakln if) is the break-in correction at time t, S _EXT is the value of the sensor data at some extremum (maximum or minimum), is the time when the extremum in the sensor data is achieved, x is a real number between 0 and 1, and τ _ι and τ ₂ are decay time constants for the break-in correction.

In some embodiments, the sensor data is current and the break-in offset current correction is computed using the double exponential formula:

where I Breakin (0 is ^me break-in current at time t, I _MAX is the maximum break-in current, ^t _MAX is the time when the maximum break-in current is achieved, x is a real number between 0 and 1 , and T\ and T ₂ are decay time constants for the break-in current.

The decay time constants have the units of time and may be any value. The decay time constants can be on the order of seconds, minutes, or hours. The parameter x adjusts the amount each of the exponentials contribute to the break-in correction. The parameter x can be any number between 0 and 1.

The break-in offset correction can be a monotonic function, preferably a monotonically decaying function of time. The break-in offset can decay to a constant value, preferably zero, over time. The break-in offset correction preferably decays within 30 minutes, within 60 minutes, within 90 minutes, within 120 minutes, within 150 minutes, or within 180 minutes.

The break-in offset can be temperature dependent or temperature independent. In some embodiments the temperature dependence is a multiplicative correction to the break-in offset. In some embodiments the break-in offset correction is computed using one of the formulas provided above (Eq. 11-12) and corrected for temperature by multiplying by a temperature-dependent function.

The temperature-dependent function can be a polynomial function, Nth root function, exponential function, hyperbolic function, logarithmic function, power function, trigonometric function, or a ratio, integral, or derivative thereof. The temperature-dependent function can be computed using any combination of the above functions, ratios, integrals, or derivatives.

In some embodiments, the temperature-dependent function is a polynomial function of temperature. The temperature-dependent function can be a 2 ^nd , 3 ^rd , 4 ^th , or higher-order polynomial, preferably a 2 ^nd order polynomial. The temperature dependent function can have the formula

Core ⁼ + b _0TC * (τ ci _0TC ) + c _0TC * (T ci _0TC ) , Eq. 13 where C _0TC is the offset temperature correction at temperature, T, and a _0TC , b _0TC , and c _0TC are real numbers.

The break-in offset can be temperature corrected by multiplying a temperature-independent break-in offset by a temperature-dependent function, such as

$TC -Breakin ⁼ ^ Breakin (0 * ^ OTC > ¾. 14 where S _TC _ _BreakIn is the temperature-corrected break-in offset, S _Brealdn (t) is the temperature-independent break-in correction at time t, and C _0TC is the offset temperature correction at temperature, T.

In some embodiments, the sensor data is current and the temperature corrected break-in offset current is computed using the formula:

I TC -Breakin = I Breakin g) * C OTC Eq. 15 where 1 _TC -Breakin ^ ^m e temperature-corrected break-in current, 1 _Break[n if) is the temperature-independent break-in current at time, t, and C _0TC is the offset temperature correction at temperature, T. In some embodiments the temperature-independent break-in current is computed using the formula: _K ( = ^ { - exp[^^]+ (l - )- exp[-^^]} Eq. 16 where I Breakin g is ^me temperature-independent break-in current at time t,

^ MAX i ^{s me} maximum break-in current, t _MAX is the time when the maximum break-in current is achieved, x is a real number between 0 and 1, and τ _χ and τ ₂ are decay time constants for the break-in current.

In some embodiments the break-in offset correction is a function, such as a polynomial function, Nth root function, exponential function, hyperbolic function, logarithmic function, power function, trigonometric function, or a ratio, integral, or derivative thereof, of both time and temperature.

B. On-Skin Offset Correction

An on-skin offset correction is provided. The on-skin offset correction is a correction that reduces the error associated from the sensor data arising after the placement of the sensor at the target site, possibly due to the presence of surface irregularities, salts, or other biological entities at the target site. The on-skin offset correction can be dependent upon time, temperature, or preferably both time and temperature. The on-skin offset correction can be an additive correction or a multiplicative correction. The on-skin offset correction is preferably an additive correction.

The on-skin offset correction can be computed using a polynomial function, Nth root function, exponential function, hyperbolic function, logarithmic function, power function, trigonometric function, or a ratio, integral, or derivative thereof. The on-skin offset can be computed using any combination of the above functions, ratios, integrals, or derivatives. In some embodiments the on-skin offset correction is computed using Nth root functions, exponential functions, or a combination thereof. The on-skin offset correction can be computed with a function having 2, 3, 4, 5, 6, or more terms. In a preferred set of embodiments the on-skin offset correction is computed using a combination of two or more exponential functions. For example, the on-skin offset correction can be computed according to the double-exponential formula:

OnSkin V ^~ '-'MAG

Eq. 17

{b + (l - 6)exp[- t / c]} + (l - f) - {d + (l - d)Qxp[- t / e]}

where S _0nSkin (t) is the on-skin offset correction at a time, t, relative to a reference time, S _MAG is the magnitude of the on-skin offset at the reference time, and b, c, d, e, f are real numbers. The constants, c and e, inside the exponential are the decay time constants for the on-skin offset correction.

In some embodiments, the sensor data is current and the on-skin offset current correction is computed using the double exponential formula:

OnSkin (Vt-)J = M.AG Eq. 18

{b + (l - 6)exp[- 1 lc]} + (l - /) · {d + (l - rf)exp[- 11 e]}

where l _0nSkin ( ) i ^{s me} on-skin offset current correction at a time, t, relative to a reference time, I _MAG is the magnitude of the on-skin current at the reference time, and b, c, d, e, f are real numbers. The constants, c and e, inside the exponential are the decay time constants for the on-skin offset current correction.

The decay time constants for the on-skin correction, c and e, have the units of time and may be any value. The decay time constants can be on the order of seconds, minutes, or hours. The parameters b, d, and / adjust the amount each of the exponentials contribute to the time dependence of the on- skin correction. The parameters b, d, and / may be any real number.

The on-skin offset correction can be a monotonic function, preferably a monotonically decaying function of time. The on-skin offset can decay to a constant value, preferably zero, over time. The on-skin offset correction preferably decays within 30 minutes, within 60 minutes, within 90 minutes, within 120 minutes, within 150 minutes, or within 180 minutes.

The on-skin offset can be temperature dependent or temperature independent. In some embodiments the temperature dependence is a multiplicative correction to the on-skin offset. In some embodiments the on- skin offset correction is computed using one of the formulas provided above and corrected for temperature by multiplying by a temperature-dependent function.

The temperature-dependent function can be a polynomial function, Nth root function, exponential function, hyperbolic function, logarithmic function, power function, trigonometric function, or a ratio, integral, or derivative thereof. The temperature-dependent function can be computed using any combination of the above functions, ratios, integrals, or derivatives.

In some embodiments the temperature-dependent function is a polynomial function of temperature. The temperature-dependent function can be a 2 ^nd , 3 ^rd , 4 ^th , or higher-order polynomial, preferably a 2 ^nd order polynomial. The temperature dependent function can have the formula

Core ⁼ + b _0TC * (τ ci _0TC ) + c _0TC * (T ci _0TC ) , Eq. 19 where C _0TC is the offset temperature correction at temperature, T, and a _0TC , b _0TC , and c _0TC are real numbers.

The on-skin offset can be temperature corrected by multiplying a temperature-independent on-skin offset by a temperature-dependent function, such as

^TC— OnSkin ^ OnSkin (t) * C _0TC , Eq. 20 where S _TC _ _0nSkin is the temperature-corrected on-skin offset, S _0nSkin (t) is the temperature-independent on-skin correction at time t, and C _0TC is the offset temperature correction at temperature, T.

In some embodiments, the sensor data is current and the temperature corrected on-skin offset current is computed using the formula:

I TC -OnSkin ⁼ I OnSkin (t * C OTC Eq. 21 where I _TC _ _0nSkin is the temperature-corrected on-skin current, I _0nShin (t) is the temperature-independent on-skin current at time, t, and C _0TC is the offset temperature correction at temperature, T. In some embodiments the temperature-independent on-skin current is computed using the formula: ¹ OnSkin V ) MAG ^' J ^' g 22

{b + {\ - b)exp[- 1 /c}} + (l - /) · {d + (l - rf)exp[- t / e}}

where I _0nSkin (t) is the on-skin offset current correction at a time, t, relative to a reference time, / _MC is the magnitude of the on-skin current at the reference time, and b, c, d, e, f are real numbers. The constants, c and e, inside the exponential are the decay time constants for the on-skin offset current correction.

In some embodiments the on-skin offset correction is a function, such as a polynomial function, Nth root function, exponential function, hyperbolic function, logarithmic function, power function, trigonometric function, or a ratio, integral, or derivative thereof, of both time and temperature.

C. Computing Analyte Concentration

The offset corrections may be used to compute the concentration of any analyte. Analytes can include naturally occurring substances, artificial substances, and/or metabolites. The analyte may be any molecule or biological species that is present in a biological fluid, such as blood, plasma, serum or interstitial fluid. The analyte can be a small molecule, protein, carbohydrate, nucleic acid, or lipid. Salts, sugar, protein, fat, vitamins and hormones naturally occurring in blood or interstitial fluids may also constitute analytes in certain embodiments. The analyte may be naturally present in the biological fluid, for example, a metabolic product, a hormone, an antigen, an antibody, and the like. Alternatively, the analyte may be introduced into the body, for example, a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based synthetic blood, or a drug or pharmaceutical composition.

The analyte may be a pharmaceutical, abused drug, a component thereof, or a metabolite thereof such as insulin; ethanol; cannabis, marijuana, tetrahydrocannabinol, or hashish; inhalants such as nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, or low molecular-weight hydrocarbons; cocaine or crack cocaine; stimulants such as amphetamines, methamphetamines, methylphenidate (RITALIN®), pemoline (CYLERT®), phenmetrazine (PRELUDI ®), or clortermine (VORANIL®); depressants such as barbituates, methaqualone, tranquilizers, diazepam (VALIUM®), chlordiazepoxide (LIBRIUM®), meprobamate (EQUANIL®), or clorazepate (TRANXENE®). narcotics such as diacetylmorphine (heroin), codeine, or morphine; anabolic steroids; and nicotine. The metabolic products of drugs and pharmaceutical compositions are also contemplated analytes. Analytes can include ascorbic acid, uric acid, dopamine, noradrenaline, 3- methoxytyramine (3MT), 3,4-Dihydroxyphenylacetic acid (DOPAC), HomovaniUic acid (HVA), 5-Hydroxytryptamine (5HT), and 5- Hydroxyindoleacetic acid (FHIAA).

The analyte to be monitored can be any analyte of interest, including, but not limited to glucose, lactate, blood gases (e.g. carbon dioxide or oxygen), blood pH, electrolytes, ammonia, proteins, biomarkers or any other biological species that is present in a biological fluid. The analyte can be cholesterol, glucose, ethanol, triglycerides, bilirubin, creatinine, urea, alpha- amylase, lactate, lactic acid, alanine aminotransferase, aspartate

aminotransferase, albumin, uric acid, fructose amine, potassium, sodium, chloride, pyruvate dehydrogenase, phenylalaninehydroxylase, purine nucleotide enzymes and phenylalanine hydroxylase, phenyl-alanine, phenyl- pyruvate, or phenyl-lactate. In preferred embodiments the analyte is glucose.

One or more of the offset corrections can be used to compute the analyte concentration. In some embodiments the sensor data is corrected using the break-in offset, the on-skin offset, or both. The offset corrections reduce the error associated with computing an analyte concentration from the sensor data. In preferred embodiments the break-in offset and on-skin offset reduce the error associated with the early -time monitoring of an analyte concentration. In some embodiments the error is reduced during the first 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, or 180 minutes of operation.

The analyte concentration can be computed from the sensor data. In some embodiments the analyte concentration is computed from the corrected data, S _A . The analyte concentration may be directly proportional to the corrected data, inversely proportional to the corrected data, exponentially proportional to the corrected data, or logarithmically proportional to the corrected data. In some embodiments the analyte concentration is computed directly using the sensor data, S s,ensor > and the offset correction, S ₀ ^ _set . The analyte concentration may be directly proportional to the sensor data, inversely proportional to the sensor data, exponentially proportional to the sensor data, or logarithmically proportional to the sensor data.

The analyte concentration may be any function of the corrected data, the sensor data, the break-in offset correction, the on-skin offset correction, or any combination thereof. The analyte concentration can be computed using a polynomial function, Nth root function, exponential function, hyperbolic function, logarithmic function, power function, trigonometric function, or a ratio, integral, or derivative thereof. The analyte concentration can be computed using any combination of the above functions, ratios, integrals, or derivatives.

In some embodiments the analyte concentration is directly proportional to the corrected data. The analyte concentration can be computed using the formula:

[A] = Slope ^■ S _A + Intercept , Eq. 23 where [A] denotes the concentration of an analyte, A, the Slope is the dependence of the analyte concentration on the corrected data, S _A , and the Intercept is the analyte concentration when the value of the corrected data is zero. The Intercept is typically 0, although this need not necessarily be the case.

In some embodiments the sensor data is current. The analyte concentration can be directly proportional to the sensor current. In some preferred embodiments the analyte concentration can be computed using the formula

[A] = Slope ^■ I _A + Intercept , Eq. 24 where [A] denotes the concentration of an analyte, A, the Slope is the dependence of the analyte concentration on the analyte current, I _A , and the Intercept is the analyte concentration when the analyte current goes to zero. The Intercept is typically 0, although this need not be the case. In particularly preferred embodiments the analyte is glucose, and the glucose concentration is computed using the formula:

[glu cos e] = Slope ^■ I _G + Intercept , Eq. 25 where [glu cose] is the glucose concentration, and I _G is the glucose current.

D. Temperature Compensation

The break-in offset correction, the on-skin offset correction, or both can be corrected to compensate for changes in temperature. In some embodiments the sum of the break-in offset correction and the on-skin offset correction is corrected to compensate for changes in temperature. Additional offset corrections, when present, may be corrected to compensate for changes in temperature. The total offset correction can be corrected to compensate for changes in temperature.

One of more of the offset corrections can be corrected to compensate for changes in temperature. The temperature correction can be an additive correction to the offset correction or a multiplicative correction to the offset correction. In preferred embodiments the temperature correction to the offset correction is a multiplicative correction. For example, the offset correction, i.e. the break-in offset correction, the on-skin offset correction, additional offset corrections, or the sum thereof, can be corrected to compensate for changes in temperature by multiplying by a temperature-dependent function. The temperature-dependent function can be a polynomial function, Nth root function, exponential function, hyperbolic function, logarithmic function, power function, trigonometric function, or a ratio, integral, or derivative thereof. The temperature-dependent function can be computed using any combination of the above functions, ratios, integrals, or derivatives.

In some embodiments the temperature-dependent function is a polynomial function of temperature. The temperature-dependent function can be a 2 ^nd , 3 ^rd , 4 ^th , or higher-order polynomial, preferably a 2 ^nd order polynomial. The temperature dependent function can have the formula

Core ⁼ 1 + b _0TC * (T a _0TC ) + c _0TC * (T a _0TC ) , Eq. 26 where C _0TC is the offset temperature correction at temperature, T, and a _0TC , b _0TC , and c _0TC are real numbers.

In some embodiments the sensor data is current and the offset correction is the sum of the break-in offset current and the on-skin offset current. In these embodiments the temperature-corrected current at temperature, T, can be computed by the formula

¹ / offset, TC = ( Vl Breakln + ^{τ 1} Ί OnSkin ) !*

r 1 + b _0TC [T— a _0TC ) + c _0TC [T— a _{0TC v} ) ] ^Ε ¾· ²⁷ where l _{offset TC} is the temperature-corrected offset current, I _BreakIjn is the break-in offset current, I _0nSkin , is the on-skin offset current, and a _0TC , b _0TC , and c _0TC are real numbers.

Other equations and/or terms used to compute the analyte concentration can be corrected to compensate for changes in temperature. For example, any term in the equations used to compute the analyte concentration from the corrected data can be corrected to compensate for changes in temperature. This can be a multiplicative correction or an additive correction, although multiplicative corrections are preferred. For example, in some embodiments where the analyte concentration is computed using a formula having the form:

[A] = Slope ^■ S _A + Intercept , Eq. 28 the Slope, the Intercept, or both can be corrected to compensate for changes in temperature. The correction can be an additive correction or a

multiplicative correction, preferably a multiplicative correction. For example, the Slope can be corrected to compensate for changes in temperature using the formula:

Slope _TC = Slope * (l + b _STC * (Τ - a _STC ) + c _STC * (Τ - a _STC f ), Eq. 29 where Slope _TC is the temperature-corrected slope, and a _STC , b _STC , and c _STC are real numbers. The temperature-corrected slope can then be used to compute the analyte concentration, i.e.

[A] = Siope _TC ^■ S _A + Intercept . Eq. 30 In some embodiments both the Slope and the Intercept are corrected to compensate for changes in temperature. The temperature-corrected slope, Slope _TC , and the temperature-corrected intercept, Intercept _TC , can both be used to compute the analyte concentration, i.e.

[A] = Siope _TC ^■ S _A + Intercept _TC . Eq. 31 In some embodiments the sensor data is current and the analyte is glucose. The glucose concentration can be computed using the formula:

[giu cos e] = Slope _TC ^■ I _{G TC} + Intercept _TC , Eq. 32 where [glucose] is the glucose concentration, Slope _TC is the temperature- corrected slope, Intercept K is the temperature corrected intercept, and I _{G TC} is the temperature-corrected glucose current. The temperature corrected glucose current can be computed, for example, by subtracting one or more temperature-corrected offset corrections from the raw current data.

Figure 1 is a flow diagram of an exemplary program for converting one or more sensor data into an analyte concentration. The program receives the sensor data 102, such as a current and a temperature. The program computes one or more offset corrections 104. The offset corrections can include a break-in offset, such as in Eq. 1 1, an on-skin offset, such as in Eq. 17, or both. The corrected analyte data is computed 106 by applying the offset correction(s) to the sensor data. The slope is corrected for changes in temperature 108, for example using Eq. 29. The analyte concentration can then be computed 110 using the temperature corrected slope and the corrected sensor analyte data.

E. Error Detection and Error Correction

Methods are provided for detecting errors and/or correcting for errors in the transdermal analyte monitoring system. The methods can include detecting an error in the state of one or more sensors, detecting if the sensor data is greater than a threshold sensor data, and/or detecting spikes or noise in the sensor data. The methods can include validating the sensor calibration, validating the detection of sensor placement onto the skin, and/or validating the sensor calibration data.

III. Transdermal Analyte Monitoring Systems

Transdermal analyte monitoring systems are provided. The transdermal analyte monitoring systems are capable of continuously monitoring one or more analyte concentrations. The transdermal analyte monitoring systems are capable of monitoring the analyte concentration for at least 12 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, or 72 hours. The transdermal analyte monitoring systems use one or more offset corrections, such as the break-on offset correction or the on- skin offset correction, to compute the analyte concentration using the data from one or more sensors. The transdermal analyte monitoring systems are capable of accurately monitoring analyte concentration during the first 4 hours, first 2 hours, first 1 hour, first 30 minutes, or first 10 minutes of usage. The offset corrections can allow the transdermal analyte monitoring system to accurately monitor the analyte concentration for at least 90% , 92%, 95%, 98%, 99% of the operational lifetime of the device. In some embodiments, the offset corrections can allow the transdermal analyte monitoring system to accurately monitor analyte concentrations for 100% of the operational lifetime of the device.

Generally, the transdermal analyte monitoring system ("TAMS") contains a sensor assembly in electrical or wireless communication with a user interface, display and/or computing device. Suitable means of communication include a wireless connection or any means for an electrical connection, such as a flexible connecting cable.

The user interface refers to the components for displaying, providing, or conveying information to the user or operator of a TAMS; components for a user or operator to control, adjust, or modify the operation of a TAMS; and components for receiving input data or information from the user or operator of the TAMS. The user interface can be a "graphical user interface", referred to as a "GUI", a command line interface, a physical interface, or a combination thereof. The user interface may contain graphical elements such as graphical displays, alphanumeric displays, liquid crystal displays (LCDs), super-twisted nematic (STN) displays, thin film transistor (TFT) displays, thin film diode (TFD) displays, light-emitting diode (LED) displays, and organic light-emitting diode (OLED) displays. The displays can be touchscreen displays, including a capacitive touchscreens and resistive touchscreens. The displays can be color or monochrome. The user interface may contain input elements such as buttons, knobs, switches, touch screens, capacitive sensing elements, or the like. The exact specifications of such a user interface will change with the growth and pace of technology, so the exemplary user interfaces and components described herein should not be seen as limiting

The TAMS is preferably used as a continuous analyte sensor that measures the concentration of an analyte of interest or analyte indicator in a body fluid (e.g. blood, serum, plasma, interstitial fluid, cerebral spinal fluid, lymph fluid, ocular fluid, saliva, or oral fluid). The TAMS is configured to be applied to an area on the skin of an animal; typically the animal is a mammal, and in the preferred embodiment the mammal is a human.

A. Sensors Assembly

The transdermal analyte monitoring system contains one or more sensor assemblies. The sensor assembly is the portion of the TAMS that provides for the detection of at least one analyte. The sensor assembly may include one or more sensors or biosensors, reference electrodes, counter electrodes, enzymes, membranes, or substrates with elements, housings, chambers, etc. for securing, containing, or positioning the elements of the sensor assembly. The term "reference electrode" means an electrode that provides a reference potential, e.g., a potential can be established between a reference electrode and a working electrode. The term "counter electrode" means an electrode in an electrochemical circuit which acts as a current source or sink to complete the electrochemical circuit. In some designs, the reference electrode and counter electrode are the same.

The sensor assembly provides for transdermal detection of one or more target analytes. The sensor assembly may have any suitable shape and size. The sensor may contain a biological element such as enzymes, antibodies, micro-organisms, biological tissue, and organelles.

The sensor assembly includes one or more sensors for the detection of an analyte. Suitable sensors include, but are not limited to, electrochemical sensors, electrical voltage sensors, electrical current sensors, temperature sensors, flow rate sensors, pressure sensors, acoustic sensors, pH sensors, accelerometers, tachometers, and concentration sensors. The sensors can include galvonometers, potentiometers, potentiostats, bipotentiostats, polypotentiostats, enzyme catalysis based sensors, redox cella,

biofunctionalized ion-selective field effect transistors, and potentiometric biosensors.

Electrochemical sensors typically include a working electrode, a reference electrode, and a counter electrode. The working electrode is typically composed of two components: a chemical recognition system and a physiochemical transducer system. The chemical recognition system provides for the selection or detection of a particular analyte or class of analytes. The physiochemical transducer system converts the chemical response into an electrical response. The method of transduction depends on the type of physicochemical change resulting from the recognition event.

The working electrode is typically an electrode at which the analyte, or an analyte indicator compound whose concentration depends upon the concentration of the analyte, is oxidized or reduced, optionally involving an electron transfer material. The working electrode preferably contains a catalytic and/or conductive material, such as pure platinum, platinized carbon, glassy carbon, carbon nanotube, mezoporous platinum, platinum black, palladium, gold, or platinum-iridium.

The sensor may contain an enzyme. Most enzymes used in this type of electrochemical sensor are oxidases that consume dissolved oxygen and produce hydrogen peroxide. Enzymes have been immobilized at the surface of the transducer by adsorption, covalent attachment, entrapment in a gel or an electrochemically generated polymer, in lipid membranes or in solution behind a semipermeable membrane. Methods for immobilizing enzymes are described in Cosnier, Biosensors and Bioelectronics, 14:443-456 (1999); Tien et al, Biochemistry and Bioenergetics , 42: 77-94 (1997); Bartlett et ah, J. Electroanalytical Chem. 362: 1-12 (1993); Scouten, Methods Enzymol. 135: 30-65 (1987); Bartlett, et al, J. Electroanalytical Chem. 224: 27-35 (1987); Brahim, et al. Michrochimica Acta. 143: 123-137 (2003); and Spahn et al, Recent Patents on Engineering 2: 195-200 (2008). Enzymes are often employed in electrochemical sensors and in fiber optic sensors.

In the preferred embodiment, the sensor assembly contains an enzyme and the enzyme is glucose oxidase. Glucose oxidase reacts with glucose to form gluconic acid and hydrogen peroxide, according to the following reaction: glucose + O2 ^ gluconolactone + H2O2. Gluconolactone hydrolyses spontaneously to form gluconic acid. Hydrogen peroxide is transported to the surface of the electrode where it reacts with the surface of the electrode and is converted into an electrical signal.

The sensor may contain antibodies. Antibodies can provide for highly specific biosensors. Antibodies can be immobilized via covalent attachment by conjugation with amino, carboxyl, aldehyde, or sulfhydryl groups.

Methods for conjugating antibodies onto electrode or potentiostat surfaces are described in Byrne et al, Sensors, 9: 4407-4445 (2009).

The sensor assembly may contain a polymer substrate. The substrate can be a hydrophilic polymer. In some embodiments the polymer forms a hydrogel. The hydrophilic polymer substrate is preferably a PEG-based hydrogel, more preferably a PEGDA-based hydrogel. U.S. Patent No.

8,224,414 to Kellogg et al. discloses some suitable PEG-based hydrogels in a sensor system. In the hydrogels, the primary component, aside from water or aqueous phase, is the polymer on which the hydrogel is based. The crosslinker, if one is used to form the hydrogel, is present in a small amount, such as from 0% to 2%, with preference given to 0.002% to 1%, and holds the hydrogel together.

The sensor assembly may contain one or more transducers. The transducer may be an electrochemical transducer such as a potentiostat or amperostat, an optical transducer, an acoustic transducer, or a calorimetric transducer. In amperometric transducers, the potential between the two electrodes is set and the current produced by the oxidation or reduction of electroactive species is measured and correlated to the concentration of the analyte. Potentiometric transducers measure the potential of electrochemical cells with low current. Field effect transistors (FET) are potentiometric devices based on the measurement of potential at an insulator-electrolyte interface. Optical fibers having the recognition element co-immobilized with a dye can be an optical transducer. The dye is typically a fluorescent dye.

The transducer in an electrochemical cell may be any transducer capable of converting the chemical/biochemical recognition event into a signal. The transducer is most commonly a potentiostat or an amperostat (galvanostat). In amperometric transducers, the potential between the two electrodes is set and the current produced by the oxidation or reduction of electroactive species is measured and correlated to the concentration of the analyte. Potentiometric transducers measure the potential of electrochemical cells with low current. Field effect transistors (FET) are potentiometric devices based on the measurement of potential at an insulator-electrolyte interface.

The sensor assembly may contain one or more additional sensors, such as temperature sensors, pressure sensors, pH sensors, humidity sensors, optical sensors, or acoustic sensors. The sensor assembly of the TAMS may be attached by any suitable means to a display or computing device. Suitable means include a wireless connection or any other means for electrical connection, such as a flexible connecting cable.

B. Computing System

The transdermal analyte monitoring system contains a computing system. The computing system can perform several tasks including, but not limited to, computing the offset corrections, temperature corrections, and analyte concentrations as described above. Computations may refer to a single step in a multi-step series of numerical and/or algebraic manipulations or may refer to entire steps, or a portion thereof, collectively as understood by context. The computing devices may in principle be any computing system or architecture capable of performing the computations and displaying, communicating, or storing the data. The exact specifications of such a system will change with the growth and pace of technology, so the exemplary computing systems and components described should not be seen as limiting. The computer system may perform additional tasks, such as performing error monitoring or noise filtering steps, performing sensor calibration steps, performing user and/or system information storage and/or retrieval, communication (either sending, receiving, or both) with other computing devices or with the user.

The computing system may have any suitable configuration, including a desktop computer, laptop computer, a personal digital assistant (PDA), a server (local or remote to the receiver), or the like. In some embodiments, a computing system may be adapted to connect (via wired or wireless connection) to a desktop computer, laptop computer, a PDA, a server (local or remote to the computing system), or the like to download data from the computing system. The computing system may be a pager- sized device and house a user interface that has a plurality of buttons and/or keypad and a liquid crystal display (LCD) screen.

In some alternative embodiments, the computing system may be housed within or directly connected to the sensor assembly to allow the sensor and the computing electronics to work directly together and/or share data processing resources. In some embodiments the user interface may also include a speaker, and a vibrator.

The computing system typically contains a processor. The processor is an electronic component that is able to execute a program or machine executable instruction. A processor may be a single general purpose single- or multi- chip microprocessor (e.g., an ARM), a special purpose microprocessor (e.g., a digital signal processor (DSP)), a microcontroller, a programmable gate array, etc. The processor may be a central processing unit (CPU). The processor may be a single-core or a multi-core processor. By referring to a system containing a processor, this should also be understood to refer to systems containing multiple processors, so-called multi-processor systems.

The computing system typically contains at least a processor and a computer readable storage medium. However, alternatively a removable computer readable storage medium can be used with a transdermal analyte monitoring system. References to a computer-readable storage medium should be interpreted as possibly comprising multiple computer-readable storage media. Various executable components of a program or programs may be stored in different locations. The computer-readable storage medium may for instance comprise multiple computer-readable storage medium within the same computer system. The computer-readable storage medium may also be computer-readable storage medium distributed amongst multiple computer systems or computing devices.

A computer readable storage medium is any tangible, non-transient storage medium which can store instructions executable by a processor or other computing device. The computer-readable storage medium may be writeable, capable of storing data from the processor or computing device. Examples of computer-readable storage media include, but are not limited to: a floppy disk, punched tape, punch cards, a magnetic hard disk drive, a solid state hard disk, flash memory, a USB thumb drive, Random Access Memory (RAM), Read Only Memory (ROM), an optical disk, a magneto-optical disk, and the register file of the processor. Examples of optical disks include Compact Disks (CD) and Digital Versatile Disks (DVD), CD-ROM, CD- RW, CD-R, DVD-ROM, DVD-RW, or DVD-R disks. The term computer readable-storage medium also refers to various types of recording media capable of being accessed by the computer device via a network or communication link. Data may be retrieved over a modem, over the internet, or over a local area network. The computer readable storage medium contains a computer program for converting data from one or more sensors into an analyte concentration. The computer readable storage medium may be insertable into and removable from the TAMS, such as a floppy disk, CD, DVD, or USB thumb drive.

The computer program contains a set of instructions for computing the concentration of one or more analytes. The computer program can contain instructions for causing the processor to carry out one or more computations necessary to compute the concentration of an analyte from one or more sensor data, offset corrections, and/or temperature corrections as defined above. The computer program can contain instructions for computing the concentration of one or more analytes using the offset corrections, temperature corrections, sensor data, and/or a combination thereof.

The computer program can contain a set of instructions for computing a break-in offset correction, an on-skin offset correction, a temperature correction, and/or a combination thereof. In some embodiments the computer program contains a set of instructions for receiving one or more sensor data and computing the one or more corrections. The sensor data can include current data from an electrochemical sensor. The computer program can contain a set of instructions for computing a break-in current offset and/or an on-skin current offset. The break-in current offset and/or on-skin current offset can be computed using one or more equations described above or a variation thereof.

The computer program can contain a set of instructions for computing one or more temperature corrections. The computer program can contain a set of instructions for computing a temperature-corrected offset. The computer program can contain a set of instructions for computing a temperature-corrected break-in offset, a temperature corrected on-skin offset, or both. The computer program can contain a set of instructions for i) computing a temperature correction such as one of the temperature- dependent functions defined above and then ii) computing a temperature corrected offset by multiplying one or more offsets by the temperature correction. The computer program can contain a set of instructions for computing a temperature-corrected analyte concentration, i.e. by multiplying the temperature corrected analyte current by the temperature corrected slope.

The computer program may perform additional tasks such as performing error monitoring or noise filtering steps, performing sensor calibration steps, performing user and/or system information storage and/or retrieval, communication (either sending, receiving, or both) with other computing devices or with the user. The computer program may contain a set of instructions for storing all or a portion of the analyte concentration data for later transmission, retrieval, and/or review.

The computer system may include a hardware interface for receiving information about the sensor assembly, such as information related to the parameters for computing one or more offset or temperature corrections. The hardware interface encompasses any interface which enables the processor of a computer system to interact with and/or control an external computing device and/or apparatus. A hardware interface may allow a processor to send control signals or instructions to an external computing device and/or apparatus. A hardware interface may also enable a processor to exchange data with an external computing device and/or apparatus. Examples of a hardware interfaces can include, but are not limited to: a universal serial bus, IEEE 1394 port, parallel port, IEEE 1284 port, serial port, RS-232 port, IEEE-488 port, Bluetooth connection, Wireless local area network connection, TCP/IP connection, Ethernet connection, control voltage interface, MIDI interface, analog input interface, and digital input interface. In some embodiments the computer system contains an interface for receiving one or more of x , τ _χ , T ₂ , b, c, d, e, f, a _STC , b _STC , c _STC a _0TC , b _0TC , and c _0TC as defined in equations 1-5 above. In some embodiments the parameters may be received through a user interface such as a GUI or an optical barcode scanner. In some embodiments the sensor assembly contains a barcode encoding the values for the one or more parameters and the parameters are received through an optical scanner or barcode scanner. C. Kits and Additional Components

The TAMS may contain additional components such as additional interface systems or control systems, such as a GUI for controlling the system and/or for accessing user data stored on the system. The TAMS may contain one or more drug delivery means for administering a therapeutic, prophylactic, or diagnostic agent.

The TAMS may be in a kit containing one or multiple sensors assemblies. Preferably the sensor assemblies are disposable (single use) and the kit contains more than one sensor assembly. For example, a kit may contain a sufficient number of sensor assemblies for a day, a week, a month (e.g. a 30-day supply) or longer. A kit may contain 2, 3, 4, 5, 6, 7, 10, 14, 21, or 30 sensor assemblies. The kit may contain instructions describing operation, maintenance, and use of the TAMS. Optionally, the kit also contains a cleaning system for cleaning the skin prior to application of the TAMS on the skin. In one embodiment, the kit contains one or more wipes, preferably pre-moistened wipes. Optionally, the kit contains a skin permeabilization device, preferably a controlled skin abrasion device.

IV. Methods of Using Transdermal Analyte Monitoring Systems

The TAMS can be used to monitor biological analytes, for example glucose blood concentrations of a user and/or to deliver therapeutic compounds, as needed. The computer readable storage media can be used with any TAMS configured to receive the computer readable storage medium and to perform one or more instructions from the computer program thereon. For example, a prediabetic or diabetic person can use the device to monitor their blood glucose concentration levels and determine if insulin is needed depending on those concentration levels. The insulin can be delivered by the user, by the device, or by another device configured to receive information from the TAMS regarding analyte (glucose) concentration and configured to administer a therapeutic agent such as insulin. Other analytes can also be monitored, and other therapeutic, prophylactic, or diagnostic agents can be administered. A. System Application

The TAMS is applied to an area on the skin (the target site) of an animal; typically the animal is a mammal, and in the preferred embodiment the mammal is a human. In some embodiments the skin at the target site is treated prior to application of the sensor assembly. The target site may be shaved to remove hair, cleaned to remove oils or other contaminants, and/or treated to enhance skin permeability. Typical methods for increasing the skin's permeability include tape stripping, rubbing, sanding, abrasion, laser ablation, radio frequency (RF) ablation, chemicals, sonophoresis, iontophoresis, electroporation, or application of permeation enhancing agents. Preferably permeability is increased in a controlled manner, such as via controlled abrasion.

In some embodiments, the target site may be treated with a permeability enhancer. Examples of permeability enhancers include, but are not limited to, compositions containing dimethyl sulfoxide (DMSO), lecithin, decyl methyl sulfoxide, dodecyl dimethyl phosphine oxide, octyl methyl sulfoxide, nonyl methyl sulfoxide, undecyl methyl sulfoxide, lauryl alcohol, diisopropyl sebacate, oleyl alcohol, diethyl sebacate, dioctyl sebacate, dioctyl azelate, hexyl laurate, ethyl caprate, butyl stearate, dibutyl sebacate, dioctyl adipate, propylene glycol dipelargonate, ethyl laurate, butyl laurate, ethyl myristate, butyl myristate, isopropyl palmitate, isopropyl isostearate, 2- ethylhexyl pelargonate, butyl benzoate, benzyl benzoate, benzyl salicylate, dibutyl phthalate, nicotinates, fatty acids, fatty alcohols, and combinations thereof.

B. Analyte Monitoring

The TAMS, once applied to the skin, can continuously monitor the concentration of one or more analytes in a noninvasive or minimally invasive manner. The transdermal analyte monitoring systems are capable of accurately monitoring the analyte concentration for at least 12 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, or 72 hours. The transdermal analyte monitoring systems use one or more offset corrections, such as the break-on offset correction or the on-skin offset correction to compute the analyte concentration using the data from one or more sensors. The transdermal analyte monitoring systems are capable of accurately monitoring analyte concentration during the first 4 hours, first 2 hours, first 1 hour, first 30 minutes, or first 10 minutes of usage (i.e.

following application on the skin site). The offset corrections can allow the transdermal analyte monitoring system to accurately monitor the analyte concentration for at least 90% , 92%, 95%, 98%, 99% of the operational lifetime of the device. In some embodiments, the offset corrections allows the transdermal analyte monitoring system to accurately monitor analyte concentrations for 100% of the operational lifetime of the device.