(702g) A Novel Insulin Delivery Approach Capable of Substantially Tight Variation of Blood Glucose Level

The potential for
successful automatic insulin delivery has entered a new era due to recent
technological advancements of insulin pumps and blood glucose sensors. However,
for full automation and control twenty four hours a day/seven days a week (24/7)
the control algorithm must be capable of tight control for major disturbances
such as meals, activity and stress. Theoretically, the superiority of feedforward control (FFC) over all
other control systems is that corrective action can be taken proactively to completely
eliminate the effects of measured disturbances on the control variable. Thus,
FFC has the potential to completely cancel the effect of any disturbance that
it models. More specifically, in this FFC approach the objective is the
development of an automatic insulin delivery system (AIDS) that nullifies the
effects of eating, activity and stress. Accomplishing this goal will
substantially reduce the variation in BGC.

While FFC has great potential, it is quite difficult to
accomplish. From a search in the literature, FFC has seen very limited
application in real processes in general and our work appears to be the only
AIDS approach. Successful FFC starts with the ability to obtain an accurate
causative model for inputs only. This is quite difficult to achieve for real
data, especially in the use of free-living data, because of high cross
correlation of inputs and changing levels of unmeasured disturbances. Our work
takes a unique approach in the use of transfer function dynamic structures with
physically interpretable parameters that are highly nonlinear in the models.
Through published work were have demonstrated the superiority of our modeling
approach causatively over all other methods theoretically as well as
experimentally. In addition, our approach is quite efficient in capturing the
variation in the response due to the measured inputs with large variations in
unmeasured inputs, even those highly correlated with measured inputs that are
modeled.

Even with an accurate FFC model, an effective FFC
algorithm is needed for its implementation into a control system. Traditional
FFC decomposes each input into a separate FFC and adds the output from each
controller to obtain controller output or in this case the insulin rate to
compensate for the model input changes. To obtain this value the model must be
linearized and the final equations can be a highly complex high order
differential equation. This work will present a simple control law that does
not decompose or linearize the model. Thus, it keeps all the properties of the
FFC model in its determination of FFC output.

In this work, 11 cases of two weeks of free living data
collection on subjects with type 1 diabetes is modeled. The study was done in
two parts. The first part takes a Wiener modeling approach which allows each
input to have separate dynamic behavior. However, while the Wiener network (WN) is an
excellent choice for the input transfer function model, in the response space,
it is limited in representing the interaction of insulin and glucose in the
blood. This drawback limits the ability to develop an accurate fit for insulin
infusion rate, which is critical to controller performance. However, to model
blood insulin and glucose interaction, one needs BIC at the sampling rate of
BGC (i.e., every five minutes with the glucose sensor used in our studies).
There is no such sensor in existence currently. To circumvent this need, we
developed a semi-coupled network (SCN) for BIC and BGC that was inspired by the
compartment modeling work of researchers in the literature. This led to the
development of an unmeasured ?pseudo? BIC variable. To our knowledge, this is
the first use of such a variable in this context of subject-specific clinical
modeling of BGC consisting only of inputs in free-living data collection. This
novel change made a substantial advancement in obtaining a better
phenomenological model and in providing a dynamic relationship between insulin
infusion rate, consumed nutrients, and BGC.

This work consists of 13 input variables of three (3)
food nutrients, seven (7) activity variables including one to measure stress,
24-hour clock time for circadian rhythm, and two (2) for insulin infusion. The
activity variables were collected using the SenseWear^®
Pro3 Body Monitoring System (BodyMedia Inc.,
Pittsburgh, Pennsylvania), which is worn on the triceps of the subject's arm.

For a FFC model, the premier measure of performance is
the correlation of the measured BGC and the fitted BGC (r_fit). The results of
splitting the data sets into 1 week of training, 4 days of validation, and 3
days of testing are reported here. The average r_fit values of the 11
cases for the WN for training, validation and testing were 0.58, 0.59, and
0.59, respectively. The average r_fit values of the 11 cases for the \SCN for
training, validation and testing were 0.64, 0.63, and 0.61, respectively. The
closeness of the values for each of the three sets is an indication that the
models did not significantly over-fit the data on unmeasured disturbances.
Given that the values for each approach are close, this is an indication that
both methods explained about the same amount of variation. While the SCN values
are slightly higher they are not substantially higher, which seems to suggest
that about all the variations due to the measured inputs were captured by both
models. Thus, given this result, the superiority of the SCN is not revealed by r_fit
but in its ability to capture or reveal true static and dynamic behavior.

Our static evaluation consisted of examining the steady
state relationships of carbohydrates (x_C), insulin
infusion rate (x_I)
and BGC level (G). This evaluation
consisted of using the SCN results of one subject and plotting x_I
versus x_C
with lines of constant G. First, the
numbers for these variables were in the ranges used by the subject. Secondly,
for a constant value of x_C (e.g., 60 gms), as G
decreased (e.g. from 300 to 100 mg/dL), x_I
increased indicating that it would take more insulin to maintain a lower BGC,
which makes phenomenological sense.

The dynamic evaluation consisted of setting x_C
to zero or setting x_I
to zero for a selected subject's model. With x_C
set to zero, the WN BGC shifted down slightly but the SCN BGC dropped to zero,
as it should. Conversely, with x_I set to zero, the WN BGC shifted up slightly
but the SCN BGC continued to rise over time, as it should. Thus, these static
and dynamic evaluations support the SCN over the WN on grounds of
phenomenological soundness.

An r_fit
value around 0.6 may not seem very high, but this value does not need to be
extremely high to make a significant difference in tightening glucose control.
This amount may represent nearly all the variation in the response that is due
to the set of inputs models. In this case the model did an exceptional job in
capturing all the variation that could be captured and whatever this level is,
the FFC has the potential to nullify all the measured inputs.

To understand the potential impact of a particular FFC
model in this work we use its fit to illustrate how the variation would be
reduced under the proposed FFC approach. More specifically, the
variability is substantially reduced, with the standard deviation dropping from
73.9 to 8.7 mg/dL, a decrease of 88.3%. This improvement
results in a level of variation similar to a person without diabetes. Thus,
this AIDS has the potential to control BGC as well as the body does for people
without diabetes.

Key words: Artificial Pancreas, Insulin
Delivery System