Testing and Tuning a Multiparameter Exercise Detection Algorithm
Phase: NA
Conditions: Type 1 Diabetes
Sponsor: Oregon Health and Science University

Protocol 2015.03 Version Date: 07/7/16
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IRB #15452
Revised:
Oregon Health & Science University
RESEARCH PROTOCOL
Protocol Title: 
Testing and Tuning a Multiparameter Exercise Detection Algorithm
Principal Investigator:
Joseph El Youssef MD
elyoussj@ohsu.edu 
Sponsor:
National Institute of Diabetes and Digestive and Kidney Diseases
BACKGROUND
The risk of hypoglycemia in individuals with type 1 diabetes (T1D) increases considerably 
during exercise. Increased glucose utilization during exercise as well as promotion of insulin 
sensitivity, both during and after exercise, have been shown to occur with prolonged periods of 
increased insulin sensitivity even after a single bout of intense physical activity. As a result, 
many patients with T1D experience fear of and reluctance to pursue physical activity, in order to 
avoid the discomforting symptoms associated with hypoglycemia.
The artificial pancreas, a device used for automatic delivery of insulin and glucagon 
subcutaneously to subjects with T1D, is paving the way to revolutionize the management of this 
disease. Already, the benefit of improved glycemic control compared to current open-loop pump 
therapy has been demonstrated in several trials. We have shown that our artificial pancreas (AP) 
algorithm dual hormone system effectively manages blood glucose in a clinic setting and our 
group specifically has shown great progress using glucagon to reduce hypoglycemic episodes 
outside of exercise 1-3. Our most recent inpatient study, as yet unpublished, shows that adjusting 
insulin and glucagon delivery during closed loop treatment, after announcing exercise, 
effectively reduces mean time below a glucose level of 70 mg/dl when compared to closed loop 
control without adjustments. We utilized initial open-loop data from this study to help devise 
dosing changes for the AP algorithm 4.
In order to prepare for a future home study, the ability to detect, grade, and classify physical 
activity so as to appropriately adjust system parameters is vital in helping to prevent exercise-
induced hypoglycemia in the home setting. Currently, our closed-loop system transmits heart rate 
and accelerometry outputs from a Zephyrlife BioPatch monitoring device to a Nexus 5 smart 
phone master controller via Bluetooth.  The algorithm then converts the heart rate and 
accelerometry data into modified estimated energy expenditure - accounting for age, weight, 
height, sex, resting and sitting heart rates - to determine if exercise is present. However, further 
data collection is needed to hone the specificity and sensitivity of the detection algorithm to 
account for a wide variety of subject characteristics and activities.
This study is designed to collect 3-axis accelerometry data and heart rate data during a variety of 
different home activities, as well as during formal exercise in both healthy subjects and subjects 
with type 1 diabetes and optionally VO2 data from a portable VO2 mask.  The data collected will 
be used to further enhance our algorithm that, in future closed-loop studies, will detect exercise 

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and automatically trigger algorithmic adjustments to reduce exercise-related hypoglycemia 
during and after exercise in individuals with T1D.
SPECIFIC OBJECTIVES
Primary Objective: To obtain accelerometer, heart rate, and optionally VO2 data from subjects 
with and without T1D during various home related activities and formal exercise for the purpose 
of training an exercise detection algorithm.
Secondary Objective: To obtain data from insulin pumps and glucose sensors from subjects 
with T1D during open-loop therapy while exercising to further define changes in glucose level 
while performing home activities and formal exercise.
HYPOTHESIS
We hypothesize that an exercise detection algorithm that utilizes accelerometer and heart rate 
data along with patient parameters, such as age, sex, weight, height, sitting and resting heart rate, 
can accurately and reliably estimate energy expenditure. We also hypothesize that certain home 
exercises may be of sufficient intensity to trigger a fall in glucose levels, which would require 
dose adjustment during closed-loop treatment of T1D in order to prevent hypoglycemia.
ENDPOINTS:
Primary Endpoints: The primary endpoints are accelerometer and heart rate data from both 
healthy subjects and subjects with T1D and healthy subjects during home activities and a 
structured exercise period.
Secondary Endpoints: Secondary endpoints include glucose data from Dexcom continuous 
glucose monitoring (CGM) systems and insulin pumps attached to subjects with T1D during 
home activities and formal exercise.
STUDY TYPE: Pilot study for data collection.
STUDY POPULATION
The study population will include healthy adults and adults with T1D who have been using an 
insulin pump for at least 6 months, ages 21 – 45 years of age. Older subjects are excluded due to 
higher risk of unrecognized coronary artery disease. Younger subjects are excluded as it is 
appropriate to assess safety first in the adult population and the current AP system has not been 
tested in the younger population. Use of an insulin pump is required so as to obtain accurate 
insulin dosing information on subjects with T1D.
Type 1 Diabetic Subject Criteria
Inclusion criteria:
Subjects meeting all of the following criteria will be considered for enrollment into the study:
a. Male or female subjects 21 to 45 years of age with a diagnosis of T1D for at least 6 
months on an insulin pump.
b. Physically active on a regular basis, i.e. at least 3 days of scheduled physical activity per 
week and willing to perform approximately 60 minutes of exercise (as determined by the 
investigator after reviewing the subjects activity level).

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c.
Willingness to follow all study procedures.
d. Willingness to sign informed consent and HIPAA documents.
Exclusion criteria:
Subjects presenting with any of the following will not be considered for enrollment in the study:
a.
Pregnancy or Lactation:
i.
For women of childbearing potential, there is a requirement for a negative urine 
pregnancy test.
b. Any cardiovascular disease, defined as a clinically significant EKG abnormality at the 
time of screening or any history of: stroke, heart failure, myocardial infarction, angina 
pectoris, or coronary arterial bypass graft or angioplasty. Diagnosis of 2nd or 3rd degree 
heart block or any non-physiological arrhythmia judged by the investigator to be 
exclusionary.
c.
Renal insufficiency (GFR < 60 ml/min, using the MDRD equation as report by the 
OHSU laboratory).
d. Hematocrit of less than or equal to 34%.
e.
History of severe hypoglycemia during the past 12 months prior to screening visit or 
hypoglycemia unawareness as judged by the investigator. 
f.
Adrenal insufficiency.
g. Any active infection.
h. Known or suspected abuse of alcohol, narcotics, or illicit drugs (except marijuana use). 
i.
Seizure disorder.
j.
Active foot ulceration.
k. Severe peripheral arterial disease characterized by ischemic rest pain or severe 
claudication.
l.
Major surgical operation within 30 days prior to screening.
m. Use of an investigational drug within 30 days prior to screening.
n. Chronic usage of any immunosuppressive medication (such as cyclosporine, 
azathioprine, sirolimus, or tacrolimus).
o. Bleeding disorder, treatment with warfarin, or platelet count below 50,000.
p. Current administration of oral or parenteral corticosteroids.
q. Any life threatening disease, including malignant neoplasms and medical history of 
malignant neoplasms within the past 5 years prior to screening (except basal and 
squamous cell skin cancer). 
r.
Any concurrent illness, other than diabetes, that is not controlled by a stable therapeutic 
regimen.
s.
Beta blockers or non-dihydropyridine calcium channel blockers.
t.
A positive response to any of the questions from the Physical Activity Readiness 
Questionnaire, see Appendix A.
u. Any chest discomfort with physical activity, including pain or pressure, or other types of 
discomfort. 
v. Any clinically significant disease or disorder which in the opinion of the Investigator may 
jeopardize the subject’s safety or compliance with the protocol.
Healthy Subject Criteria
Inclusion Criteria:

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a.
Male or female subjects 21 to 45 years of age.
b. Physically active on a regular basis, i.e. at least 3 days of scheduled physical activity per 
week and willing to perform approximately 60 minutes of exercise (as determined by the 
investigator after reviewing the subjects activity level).
c.
Willingness to follow all study procedures.
d. Willingness to sign informed consent and HIPAA documents.
Exclusion criteria:
a.
Pregnancy or Lactation:
a.
For women of childbearing potential, there is a requirement for a negative urine 
pregnancy test.
b. Any history or evidence of renal insufficiency, adrenal insufficiency, liver disease or 
anemia. 
c.
A history of cerebrovascular disease or coronary artery disease (or angina) regardless of 
the time since occurrence.
d. Congestive heart failure, New York Heart Association (NYHA) any class.
e.
Diagnosis of 1st, 2nd or 3rd degree heart block or any arrhythmia judged by the 
investigator to be exclusionary.
f.
Any condition which, in the opinion of the investigator, makes it difficult to engage in 
vigorous physical activity. 
g. Any active infection.
h. Severe peripheral arterial disease characterized by ischemic rest pain or severe 
claudication.
i.
Active alcohol abuse, substance abuse, or severe mental illness (as judged by the 
principal investigator).
j.
Active malignancy, except basal cell or squamous cell skin cancers.
k. Major surgical operation within 30 days prior to screening.
l.
Seizure disorder.
m. Bleeding disorder, or treatment with warfarin.
n. Use of an investigational drug within 30 days prior to screening.
o. A positive response to any of the questions from the Physical Activity Readiness 
Questionnaire.
p. Any chest discomfort with physical activity, including pain, pressure or other types of 
discomfort.
q. Any reason the principal investigator deems exclusionary.
STUDY RECRUITMENT
Subjects will be recruited from OHSU clinics, from flyers to be posted in approved places at 
OHSU, or from the OHSU Subject Recruitment website. Records from OHSU Harold Schnitzer 
Diabetes Clinic patients may be screened to find potential TID subjects. Subjects will also be 
recruited from a list of subjects who participated in past OHSU studies, past studies involving 
Drs. Castle or El Youssef, from the OHSU diabetes research registry and www.clinicaltrials.gov. 
Up to 60 subjects may be screened in this study with up to 40 subjects enrolled into the study at 
OHSU, split 60-80% healthy subjects and 20-40% subjects with T1D.

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Non-English speaking T1D subjects will not be recruited since this protocol will require use of a 
device and mobile software (Dexcom G4, Dexcom Share or Dexcom G5 Mobile) that does not 
have non-English versions available yet for users.
Withdrawal Criteria
The subject may withdraw at will at any time or at the discretion of the Investigator.
A subject must be withdrawn if the following applies:
1. Hypoglycemia, in T1D subjects, during the treatment period posing a safety problem as 
judged by the investigator.
2. Hyperglycemia, in T1D subjects, during the treatment period posing a safety problem as 
judged by the investigator.
3. Protocol deviation having influence on efficacy or safety data as judged by the 
Investigator.
4. Substantial and repeated non-compliance with trial procedures.
5. Pregnancy.
6. Intention of becoming pregnant.
OVERALL STUDY DESIGN
The aim of the study is to determine if accelerometer, heart rate, and VO2 data can be utilized to 
enhance our exercise detection algorithm for use in our closed-loop system. The VO2 mask may 
be worn by subjects during a single exercise visit to determine the actual energy expenditure of 
each activity using metabolic equivalents (METs).  Each subject may wear one or more 
monitoring devices which will be transmitting heart rate and accelerometer data to a master 
controller, such as a Nexus 5 smart phone.  The master controller may be running an algorithm to 
detect and grade exercise, and will be collecting data for offline analysis and algorithm tuning. 
This device will not be connected to a glucose sensor, a pump delivering insulin or a pump 
delivering glucagon for the purpose of managing blood sugar in subjects with T1D.
STUDY DETAILS
Visit 1: Screening
Screening will take place at OHSU’s Harold Schnitzer Diabetes Health Center clinic Prior to any 
procedures, the consent/authorization form will be reviewed and signed, with a copy of the 
consent/authorization form given to the subject. The original will be kept for the source 
document. This visit will take approximately 1.5 hours for healthy subjects.
In all subjects, study personnel will review medical history and medications, and fill out the 
Physical Activity Readiness Questionnaire (Appendix A); height, weight, pulse, blood pressure, 
and a resting EKG will be obtained; a study investigator will perform a physical examination, 
excluding breast and pelvic exams; and females of child-bearing potential will take a urine 
pregnancy test, which must be negative to participate. A study investigator will assess 
inclusion/exclusion criteria and review the subject’s medical record for clarification as needed.  
Subjects may be asked to be fitted with a portable VO2 mask and will wear the mask for 
approximately 1 hour to obtain accurate baseline data. Subjects will be asked to abstain from 
food, caffeine and alcohol for approximately 3-4 hours prior to screening to ensure accurate VO2 
baseline data. A three digit subject ID number will be assigned to each subject. The TID subjects 

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and the healthy subjects will be randomized separately to ensure that there are equal numbers 
within each arm of the study, as follows:
 
1) Aerobic exercise at OCTRI followed by activities of daily living and resistance exercise 
at the POC lab, or
2) Activities of daily living and resistance exercise at the POC lab followed by aerobic 
exercise at OCTRI
This randomization is intended to help address if glucose changes in subjects with T1D are 
affected by either the order of structured exercise and activities of daily living (ADLs) or aerobic 
vs. resistance exercises.
T1D Subject Screening Specifics: This screening will take approximately 2 hours. At the 
beginning of screening, after consent has been signed, subjects with T1D will be asked to test 
their blood sugar using their own meter and strips. Venous blood samples will be taken for 
complete blood count, and complete metabolic panel (including creatinine, liver panel, and 
electrolytes) labs. If subjects have had the aforementioned labs performed within the 3 months 
prior to the intended date of Visit 2 and we can access the results, venous blood samples will not 
be taken. These subjects will be fitted with a Dexcom G4,Share, or Dexcom G5 Mobile glucose 
sensor and short device training will be performed at the screening. The subjects that require 
blood tests will be asked to return for an approximately 15-30 minutes sensor training and 
insertion visit if their lab results determine that they pass screening. 
Visit 2: Exercise Study 
For all subjects, the exercise visit will occur within 12 weeks of screening. For T1D subjects, the 
exercise visit will occur no less than 24 hours and no more than 5 days from the time of sensor 
insertion. 
Subjects with T1D will always be asked to check their capillary blood glucose (CBG) before 
driving to the clinic and to bring a snack in the car in case hypoglycemia does occur (in which 
case, subjects must park and treat the hypoglycemia).
This visit will take approximately 4 hours and take place at the OCTRI Clinical research unit as 
well as the Biomedical Engineering Point of Care (BME POC) Lab. A study technician and 

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investigator will always be present in the room throughout the study for safety purposes. On the 
day of the study, subjects will be instructed to have breakfast at 6 am. 
Subjects will be instructed to arrive at OCTRI or BME POC lab around 8 am depending on their 
randomization group. Subjects with T1D will measure their capillary blood glucose (CBG) with 
their own glucose meter at the beginning of the visit. Subjects with T1D will continue their 
normal basal insulin delivery using their own pump and will be allowed to adjust insulin delivery 
during the structured exercise period as they normally would at home. All subjects will be fitted 
with a device to record accelerometer and heart rate data, and may be fitted with the portable 
VO2 mask.
During the aerobic exercise period and resistance exercise period, there will be defined rules for 
stopping, including:
1) If the subject feels unwell,
2) If a subject with T1D develops hypoglycemic symptoms, such as excessive sweating, 
shaking/tremors, palpitations, feelings of dread or panic, light-headedness, nausea, 
difficulty concentrating or the like,
3) If the subject develops chest pain/pressure,
4) If the subject develops undue shortness of breath,
5) If the maximum heart rate (defined as 220 – the subject’s age) is reached or exceeded,
6) For patient preference.
The study technician and physician will accompany the subject up and down the tram between 
the two portions of the visit (from OCTRI to CHH or CHH to OCTRI).
Aerobic Exercise: During the aerobic exercise event, all subjects will perform exercise on a 
treadmill or cycle ergometer in three 15 minute periods each with at least 10 minutes of rest 
between each exercise period. Exercise intensity will vary between periods to achieve different 
energy expenditures, which may be determined based on VO2 measurements. Subjects with T1D 
will do a CBG prior to exercise and will not start exercising if glucose is <70 mg/dl; they will be 
given 15-20 grams of carbohydrates for CBG values of <70 mg/dL and CBG retested in 15 
minutes. A code cart is on site at OCTRI and a code team is available by page at all times. After 
completion of the exercise, T1D subjects will complete another CBG sample and have it 
reviewed by an investigator. These subjects will be provided with a snack after testing if 
necessary to avoid post-testing hypoglycemia. 
ADL and Resistance Exercise: T1D subjects will complete a CBG prior to starting this exercise 
period if ADL and resistance exercise is their first exercise of Visit 2. If the T1D subject has just 
come from aerobic exercise, they will not need to complete a CBG prior to starting this period. 
Activities simulating normal household activities will be completed in the Point of Care Lab. 
These activities may include:
1) sitting on a chair or lying on a bed,
2) washing dishes or folding laundry,
3) sweeping the floor or vacuuming,
4) organizing a room or adjusting furniture in a room,

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5) scrubbing the carpet or the walls and/or
6) going up and down flights of stairs.
Each activity will be performed between 5-15 minutes. After the ADL are complete, subjects 
will perform resistance exercises such as straight-leg raises or wall sits for approximately 20 
minutes. All items necessary for performing these activities are provided in the POC lab, and 
subject safety throughout all activities will be ensured by coordinator observation. A CBG will 
be completed at the end of this exercise portion if the subject has already completed aerobic 
exercise. If the subject has yet to complete the aerobic portion of the visit, they will not take a 
CBG measurement at this time and will instead complete one just prior to starting aerobic 
exercise.
After the study is completed, the subject will have all devices removed.  Subjects with T1D will 
have a CBG sample taken and reviewed by an investigator. If necessary, oral carbohydrates will 
be given for values below 70 mg/dl, and an insulin bolus will be given if deemed appropriate by 
the study investigator for values above 250 mg/dl. Study staff will download the data from the 
subject’s personal insulin pump.
Visit 3: Study Follow-up
The study follow-up visit will be conducted by phone call to the subject at the phone number 
obtained during screening, to determine the general post-discharge status of the subject.  The 
subject will be contacted 48 hours (+/- 24 hours) after the exercise portion of the study takes 
place.
CONFIDENTIALITY AND PROTECTION OF HUMAN SUBJECTS
Risks and Benefits:
Risks: The risks of the protocol procedures are considered minor. It should be noted that a fully 
trained physician will be in constant attendance on the research ward. The likelihood of 
significant harm is quite low. Risks of exercise include falls, sprains, bruises, very low risk of 
bone fractures and head trauma.
In subjects with T1D, there is a small risk of sensor fracture, and in such a case, a piece of the 
sensor could be left in the tissue after sensor removal. For this reason, the study investigator will 
inspect each removed sensor for the possibility of breakage or fracture. Any evidence of sensor 
breakage will be recorded and reported to FDA and the sensor company.
Benefits: The subject may not directly benefit from being in this study; however, their 
participation may help to advance automated insulin and glucagon delivery technology.
Monitoring Entity:
This investigation will be monitored by the principal investigator Joseph El Youssef, MD.  Dr. El 
Youssef has no commercial interest in any of the companies which manufacture any of the 
devices used in this study. 
Data Collection:

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Subject privacy will be protected by using a three digit identifying number to code study 
documents. Study staff will record data required by the protocol onto the Case Report Forms 
(CRF). Case report forms (CRF) for this study will be entered into REDCAP, a clinical research 
electronic data repository housed at Oregon Health Science University and administered by the 
Oregon Clinical and Translation Research Institute (OCTRI).  Investigators and research 
coordinator will verify that the procedures are conducted according to the approved protocol. All 
paper source documents will be kept in a locked cabinet for a minimum of five years. Original, 
completed CRF’s will be kept with the PI in a designated repository. All data from CRF’s will 
subsequently be entered into the authorized electronic REDCAP database
Recording of Data:
Investigators and staff will record data collected during the clinical trial on the CRF’s. Case 
report forms (CRF) for this study will be entered into REDCAP, a clinical research electronic 
data repository housed at Oregon Health Science University and administered by the Oregon 
Clinical and Translation Research Institute (OCTRI). The REDCAP CRFs will include:
1. Screening form
2. Exercise Study form
3. Phone Update Form
4. Adverse Event form
5. Serious Adverse Event form
6. Concomitant Medications
The Principal Investigator may authorize other personnel to make entries in the CRF.
Data Analysis:
All data will be actively streamed to the master controller on the Nexus 5 phone and will be 
analyzed online with a currently described exercise detection algorithm 5. The algorithm results 
will be compared to data from the VO2 mask in order to assess the sensitivity and specificity of 
the algorithm, and may also be used to improve upon the parameters of the algorithm. 
Additionally, glucose data from CGM devices will be analyzed for the rate of change of glucose 
(in mg/dl/min) during exercise events in order to help quantify this for different activities. Model 
analysis with a published non-linear model of glucose regulation 6 will help track glucose 
changes with respect to insulin delivered and activity level.
Monitoring Procedures:
This protocol is written in accordance with the principles established by the 18th World Medical 
Assembly General Assembly (Helsinki, 1964) and amendments and clarifications adopted by the 
29th (Tokyo, 1975), 35th (Venice, 1983), 41st (Hong Kong, 1989), 48th (Somerset West, South 
Africa, 1996), 52nd (Edinburgh, 2000), 53rd (Washington, 2002), 55th (Tokyo, 2004), and 59th 
(Seoul, 2008) General Assemblies.  The investigator will ensure that the study described in this 
protocol is conducted in full conformance with those principles, the protocol, current FDA 
regulations, ICH Good Clinical Practices (GCP) guidelines, Good Laboratory Practices (GLP) 
guidelines, local ethical and regulatory requirements, including the Federal Food, Drug and 
Cosmetic Act, U.S. applicable Code of Federal Regulations (title 21), any IEC requirements 
relative to clinical studies. 

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Should a conflict arise, the investigator will follow whichever law or guideline affords the 
greater protection to the individual subject. The investigator will also ensure thorough familiarity 
with the appropriate use and potential risks of use of all study devices as described in this 
protocol, prior to the initiation of the study.
Unanticipated problems will be detected by reviewing descriptions of known or foreseeable 
adverse events and risks in the IRB-approved research protocol and the current IRB approved 
consent form, any underlying disease or conditions of the subject experiencing the adverse event, 
a careful assessment of whether the adverse event is related or possibly related to the subject’s 
participation in the study. Triggers for reporting unanticipated problems are seizure, 
hospitalization, death or any other occurrence considered serious by the PI.
Any adverse event and/or unanticipated problem (UP) will be reported to the investigator 
monitor immediately by one of the investigators. One of the investigators will always be on-site 
during the studies and will write up a description of the adverse event/unanticipated problem. 
Deaths and potentially life-threatening events will be reported to the IRB within seven calendar 
days after the PI learns of the event. All other UPs must be reported to the IRB within fifteen 
calendar days.  The report will be submitted to the IRB by the principal investigator or study 
coordinator. All summary of all UP's and adverse events will be submitted with the continuing 
review. 
Confidentiality Procedures:
To protect confidentiality, standard institutional practices will be followed as described in the 
OHSU Information Security and Research Data Resource Guide 
(http://ozone.ohsu.edu/cc/sec/isg/res_sec.pdf) to maintain the confidentiality and security of data 
collected in this study. Study staff will be trained with regard to these procedures. Upon 
enrollment, subjects will be assigned with a three-digit code that will be used instead of their 
name, medical record number or other personally identifying information. The key associating 
the code and the subject’s personal identifying information will be restricted to the PI and study 
staff. The key will be kept secure on a restricted OHSU network drive in a limited access folder.  
Electronic files for data analysis will contain only the subject code.  Access to data/specimens is 
restricted to study personnel and requires OHSU ID/password authentication. Paper files will be 
stored in locked filing cabinets in restricted access offices at OHSU.  Electronic data is stored on 
restricted drives on the OHSU network or stored on encrypted computers as well as on the web-
accessible REDCap database housed on an OHSU secure server. User passwords will be changed 
every 3 months and a firewall will be enabled at all times.  After the study, source documents 
will be maintained at the participating clinical center (or offsite record storage facilities) 2 years 
after a marketing application is approved for our group's artificial pancreas/decision support 
device since the data from this study will be included in future software revisions or 
discontinuance of pursuit of marketing approval.   At the end of the study, an electronic copy of 
the database will be provided on a CD for long-term storage under lock.

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APPENDIX A

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REFERENCES 
1. Castle JR, Engle JM, El Youssef J, et al. Novel use of glucagon in a closed-loop system for 
prevention of hypoglycemia in type 1 diabetes. Diabetes Care. 2010;33(6):1282-1287. doi: 
10.2337/dc09-2254; 10.2337/dc09-2254. 
2. Jacobs PG, El Youssef J, Castle J, et al. Automated control of an adaptive bihormonal, dual-
sensor artificial pancreas and evaluation during inpatient studies. IEEE Trans Biomed Eng. 
2014;61(10):2569-2581. doi: 10.1109/TBME.2014.2323248 [doi]. 
3. Jacobs PG, El Youssef J, Castle JR, et al. Development of a fully automated closed loop 
artificial pancreas control system with dual pump delivery of insulin and glucagon. Conf Proc 
IEEE Eng Med Biol Soc. 2011;2011:397-400. doi: 10.1109/IEMBS.2011.6090127; 
10.1109/IEMBS.2011.6090127. 
4. Jacobs PG, Resalat N, El Youssef J, et al. Incorporating an Exercise Detection, Grading, and 
Hormone Dosing Algorithm Into the Artificial Pancreas Using Accelerometry and Heart Rate. J 
Diabetes Sci Technol. 2015;9(6):1175-1184. doi: 10.1177/1932296815609371 [doi]. 
5. Zakeri I, Adolph AL, Puyau MR, Vohra FA, Butte NF. Application of cross-sectional time 
series modeling for the prediction of energy expenditure from heart rate and accelerometry. J 
Appl Physiol (1985). 2008;104(6):1665-1673. doi: 10.1152/japplphysiol.01163.2007 [doi]. 
6. Hovorka R, Canonico V, Chassin LJ, et al. Nonlinear model predictive control of glucose 
concentration in subjects with type 1 diabetes. Physiol Meas. 2004;25(4):905-920. 

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