The Role of Process Systems Engineering in the Quest for ... [Compatibility Mode].pdfNormalization...
Transcript of The Role of Process Systems Engineering in the Quest for ... [Compatibility Mode].pdfNormalization...
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The Role of Process Systems Engineering in the Quest for the Artificial Pancreas
Francis J. Doyle IIIDepartment of Chemical Engineering
Biomolecular Science and Engineering ProgramInstitute for Collaborative Biotechnologies
UCSB
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Type 1 Diabetes Mellitus• About one in every 400 to 600 children and adolescents has type 1
diabetes mellitus (T1DM)– National Diabetes Fact Sheet, 2005,
Centers for Disease Control and PreventionCenters for Disease Control and Prevention
• Complications of T1DM reduce life expectancy by 20 years through micro- and macro-vascular disease– Heart disease and stroke– Blindness– Kidney disease
Nervous system disease– Nervous system disease
• Evidence that intensive insulin therapy (IIT) reduces complications– Diabetes Control and Complications Trial Research Group, 1993p p,
• Increased hypoglycemic events with IIT– Diabetes Control and Complications Trial Research Group, 1993
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The Cost of Diabetes
(billions of $)Costs of Diabetes
[ADA 2003]
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Glucose Homeostasis
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(i) Automatic Control
The Glucose – Insulin “Loop”
?(i) Automatic Control
(iii) Efficient Solution
(ii) Day‐to‐day Control?
Glucose InsulinDeliveryMeasurement Delivery
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Normalization of Glycemia
Healthy Individual (MD) Optimized Type 1 Patient
Figure 1 Twenty four hour continuous g lucose t racing o f a subject without diabetes. This isthe level of glucose regulation we aim for in our deve lopment of a closed-loop controller for
Figure 12 Twenty four hour continuous glucose tracing for a subject with type 1 diabetes mellitus after correcting basal and bolus insulin profiles. Note elimination of glucose
an artificial pancreas. Unpublished data from NIH funded study (R01 -DK068706, R01-DK068663).
excursions, hyper- and hypoglycemia.Unpublished data from NIH funded study (R01-DK068706, R01-DK068663).
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Sampled Data Sampled Data –– Blood GlucoseBlood Glucose
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UCSB/Sansum Approach
Feedback control algorithmCore insulin delivery algorithm
Ellingsen et al., 2009, J. Diabetes Sci. Tech.; Percival et al., submitted, 2009
Hypoglycemia predictionAlarms and pump shut‐off
Dassau et al., 2008, Diabetes
Meal detectionAugment control algorithm
Dassau et al., 2008, Diabetes Care
Iterative learning controlAccount for intra‐subject variations
Zisser et al 2005 Diabetes Technol Ther ; Wang et al 2009 IEEE Trans Biomed Eng 2009
Dassau et al., 2008, Diabetes Care
Hardware‐in‐the‐loop trialsTesting communication protocols of off‐the‐shelf devices
Zisser et al., 2005 Diabetes Technol. Ther.; Wang et al., 2009, IEEE Trans Biomed Eng, 2009
Dassau et al 2009 Diabetes Technol TherDassau et al., 2009, Diabetes Technol . Ther
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Gl cose SensingGlucose Sensingand Insulin Delivery
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Current State of the Art:Self-Monitoring Blood Glucose Meters (SMBG)
[Graham, P&T, 2005]
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Benefits of Continuous Glucose Monitoring
Standard Blood Glucose Monitoring Continuous Glucose Monitoring
Highs Missed
Lows Missed
Source: Medtronic Diabetes modified by H. Zisser
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Receiver for Sensor
Source: DexCom,Inc.
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Archival Data Analysis
Source: Medtronic Diabetes
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Continuous Subcutaneous Insulin Infusion (CSII)
• Patients can easily accommodate metabolic changesS t b l t• Set basal rate
• Deliver manual boluses
http://www.endotext.org/diabetes
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Opportunities for Process S stems EngineeringProcess Systems Engineering:
SMBG Systems
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Meal Bolus Dosing Analogy: Run-to-Run Control[Doyle III et al., 2001; Zisser et al., 2005; Owens et al., 2006]
• Emerged from robotics and semiconductor processing problems where “repetition” is key– emphasis on measurement-based framework– batch-to-batch optimization ⇒ iteratively converge to optimal input
profile in fewest number of (sub-optimal) runst i l t i t ( d diti ) iti l l t f th– terminal constraints (end-conditions) are a critical element of the optimization problem
Concept: Use meal cycle (run)• Concept: Use meal cycle (run) to manage diabetes
max max
min min
( 1) ( ) min(0, ( ))
( 1) ( ) max(0, ( ))
rT
rQ
T k T k K G G k
Q k Q k K G G k
+ = + −
+ = + −
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Clinical Evaluation of Run-to-Run Control
Glucose (60 min) GlGlucose (60 min)
Insulin Amount
Glucose Bounds
Summary of Trial Results: • 40% dramatic improvement Insulin Amount
Day
• 40% dramatic improvement• 30% maintained normoglycemia• 30% complications
Trial Results Suggested:
Glucose (90 min)
Trial Results Suggested:• Changing timing is inconvenient for subject, and has negligible impact• Fixed timing of measurements is not realistic to meet consistently
Insulin Timingg
Day
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Modified Algorithmrate of
postprandial glucose rise
insulin meal bolus
• Only changing insulin dose, timing always fixed to the beginning of the meal
• Still require two post-meal measurements– First measurement 60-90 minutes after the start of the meal– Second measurement 30-60 minutes after the first
For each meal denote these times as:– For each meal, denote these times as:TB1, TB2, TL1, TL2, TD1, TD2
• Specific uncertainties:– Measurement timing
M t i
• Sketch of robustness analysis
– Measurement noise
– Meal timing
– Meal carbohydrate contentMeal carbohydrate content
– Meal estimate
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Clinical Evaluation of New Algorithm
• 11 subjects with type 1 diabetes & CSII pumps
• Phase 1– Optimized basal rates– Brought out of control (1h post-prandial 170–200 mg/dl)– Lunch only– Carbohydrate content kept constant– Algorithm adjusted dosing over 2 weeks
• Phase 2– All three meals– Carbohydrate content varied– Algorithm adjusted dosing over 2–3 weeks
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Challenge in Data Clustering
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Medically-Inspired Performance Measure
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Modifications for Phase 2
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Clinical ResultsClinical Results
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Implementation of Run-to-Run Controlleron PDA Platformon PDA Platform
[Gema Garcia Saez and colleagues]
Run-to-RunAlgorithm
ED
ICIN
E
VE
R
MONITORING DATA
Patient
TE
LE
ME
SER
VMONITORING DATA
GPRS
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Opportunities for P S t E i iProcess Systems Engineering:
CGM Systems
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Model-Based Control Approach for Diabetes[Parker Doyle III Peppas IEEE Trans Biomed Eng 1999][Parker, Doyle III, Peppas, IEEE Trans. Biomed. Eng., 1999]
Model-basedAlgorithmD i d
Controller Patient
AlgorithmDesiredGlucose Level GlucoseInsulin
-
ModelKalman Filter -
UpdateFilter
Compartmental Model
Key tenet of Robust Control Theory:Key tenet of Robust Control Theory:Achievable performance is directly tied to model accuracy
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Pumps and Sensors Communicate to a Shared Platform ‐APS
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Artificial Pancreas (Artificial Pancreas (ββ‐‐cell) Software cell) Software
Human Machine Interface
Sensor & Capillary
Rate or amountCapillarymeasurements
Deliveredinsulin
Insulin delivery
Event log
Physician override
Capillary BG
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Hardware-in-the-Loop Testing
• A complete artificial β-cell system testing platform, allowing:p , g
Systematic analysisComponent Verification and ValidationComplete system V&VPnP for in silico patientsPnP for in silico patientsPnP for control algorithms
• Realistic virtual clinical trial
Dassau et al., 2007, 7th DTM, San Francisco CA, USADassau et al., 2008, "In Silico Evaluation Platform for Artificial Pancreatic β−Cell Development – a Dynamic Simulator for Closed-Loop Control with Hardware-in-the-Loop." Diabetes Technol Ther., 2009
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Algorithm Engineering MPC for T1DM
• Patient Model Identification
• Disturbance Estimation (i.e., meals)
• Programming Implementation (mpMPC)g g p ( p )
• Safety Constraints (Insulin-on-Board)
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Meal Detection
Lunch Detection < 30 min
2 Hours
13 y.o. male, A1c=8.8
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Classes of Control Action for MealsF df d t l• Feedforward control– User intervention: clicking a button, thus initiating an insulin
bolus
• Strictly feedback method• Totally automated: the algorithm will respond only after a
sufficiently large rise in glucosesufficiently large rise in glucose
• Discrete meal detection• Safety net: this will trigger an insulin bolus as part of an
MealMealFeedforwardFeedforward MealMeal Strictly FeedbackStrictly Feedback
MealMealDiscrete meal detectionDiscrete meal detection
algorithm using continuous feedback from a CGM
MealMeal
1407060
300
1407060
300MealMeal
1407060
300
0
60
0 0
DetectionDetection
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Meal Detection – Voting Algorithm• Data acquisition
CGMS Data• Data acquisition• Algorithms:
– Glucose profile estimation by Kalman Filter (KF) G
Kalman Filter EstimationG
G
(KF), GKF
– Glucose rate (velocity) estimation using Backward Difference G’BD& KF ,G’KF , (GKF)’
BD
ROC Calculation (BD)
G’KF G”KF
GKF
( KF) BD
– Glucose velocity rate (acceleration) estimation by KF, G”KF
• Detection procedure:Detection AlgorithmNext
G’BD , (GKF)’BD
p– Satisfying threshold conditions – Heuristics– Tradeoff between speed of response and
go t
Voting system
data point
Nop paccuracy in flagging a meal
• Voting algorithm– Minimizing false detections
system
l fl
Yes
g• Meal flag to the controller Meal flag
[Dassau et al., Diabetes Care, 2008]
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Detection of a Single Meal
Meal flagMeal flag
~12 minBreakfastBreakfast 1212 min.min.
~12 mg/dL 9 9 min.min.10 10 min.min.12 12 min.min.
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Multi-Parametric Programming Implementation[Percival et al., AIChE, 2008]
• Biomedical devices are subject to stringent FDA regulation
Restrictions on online optimization
[ , , ]
– Restrictions on online optimization permissible
– Prior risk analysis mandatory
• MPC is transformed into a multi parametric• MPC is transformed into a multi-parametric program (mpMPC)
– Offline optimization over state-space region of interest
• Lookup table of optimal control laws– Online optimization
• Determine critical region in state-space• Evaluate an affine function of the state vector
• Simulated response to announced 60 g 00:00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00:0050
100
150
200
250
Glu
cose
(mg/
dL)
Closed-loopSetpointDesired rangePredicted outputOpen-loop
• Simulated response to announced 60 g CHO meal
– Bolus-style controller response– Hyperglycemia and hypoglycemia avoided– Euglycemia restored in under three hours
00:00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00:00
00:00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00:000
2
4
6
8
Insu
lin d
eliv
ery
(U/h
)
Insulin deliveredBasal setpointPredicted moves
1000
1500
on– Euglycemia restored in under three hours– Variations in the state vector change the
critical region used to evaluate the control law
00:00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00:000
500
1000
Reg
io
Time
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Controller Derivation[Dua, Doyle III, Pistokopoulos, IEEE TBME, 2006]
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Safety Constraints – Insulin on Board (IOB)
Residual insulin (IOB) remains active for up to 8 hours
Clinicians and bolus “wizards” factor in IOB
Constraint formulationChoose IOB curve
Time–Action Profile Of Insulin Glargine Following Subcutaneous Injection. Glycemic clamp study. [Taken from Lepore et al Diabetes 49:2142 2148 2000]
Calculate IOBAllow insulin for correctionAllow insulin for mealsC t i t l l ith 60
80
100
]
2 hour curve3 hour curve4 hour curve5 hour curve6 hour curve
al, Diabetes 49:2142–2148, 2000]
Constrain control algorithm
0 1 2 3 4 5 6 7 80
20
40
60
IOB
[%]
7 hour curve8 hour curve
0 1 2 3 4 5 6 7 8Time [hr]
Walsh and Roberts, Pumping Insulin, 2006Zisser et al., Diabetes TechnolTher, 2008Ellingsen et al., J Diabetes SciTechnol, 2009
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Clinical Evaluation
FDA requirementsInvestigational Device Exemption (IDE)Detailed proof of safety of protocol/softwareMaster file already acknowledged for APS
Phase I – in silico trialUVa-Padova simulation platform300 virtual subjectsMaster file already acknowledgedMaster file already acknowledgedEvaluate same clinical protocol
Phase II – human subject studiesInitial studies underway in IsraelPlanned studies in Santa Barbara in late 2009Large international trial (multi site) planned for 2010Large international trial (multi-site) planned for 2010
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In Silico Trial Results[100 adult subjects][100 adult subjects]
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Clinical Trial Results[Schneider Children’s Medical Center of Israel, Tel Aviv]
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Pieces of the Puzzle Are Coming Together
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Looking Towards the Future:
Safety Issues
Human VariabilityHuman Variability
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Hypoglycemia Prediction• Intensive insulin therapy has an
inherent risk of nocturnal hypoglycemia Begins alarming at
11:39 PM withHad been alarming since 2:39 AM when glucose was 63– No response to any alarm
– Threshold alarms are insufficient
11:39 PM with glucose of 64 mg/dL.
AM when glucose was 63 mg/dL, lowest 50 mg/dL.
Prediction of pending hypoglycemic event & pump suspension
Seizure
DirecNet
Dassau et al. 68th ADA meeting San Francisco CA, 06.08.08
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Hypoglycemia Prediction System[collaboration w/ Bruce Buckingham, Stanford Medical]
• A Hypoglycemia Prediction System (HPS) was developed using data derived from 21 Navigator studies which assessed Navigator g gfunction over 24 hours in children with Type 1 diabetes in clinical research centers (CRC)*
• The HPS functionality was confirmed using a separate dataset from 22 CRC admissions of T1DM subjects– mean age = 20 years (range 6 -38)
hypoglycemia was induced by gradual increases in the basal insulin– hypoglycemia was induced by gradual increases in the basal insulin infusion rate by a mean of 180%
– 18 of the 22 subjects (82%) reached a glucose value of ≤ 60 mg/dL
*DirecNet, Diabetes Care
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Variability in the Human Body: Stress Effects
Clinical evaluation of the effect of Prednisone[Bevier et al 2007][Bevier, et al., 2007]
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Summary• Process systems engineering offers tremendous capability to
enable the artificial pancreas
• Promising technologies:– Run-to-run control
M d l di ti t l– Model predictive control– Parametric programming implementation
M h ll till i• Many challenges still remain:– Patient model identification– Reliable (long-term) sensors– Transport and site issues– Patient variability (incl. stress, activity, etc.)– Regulatory issues
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Acknowledgments
• Bob Parker [Pitt] • Camelia Owens [FDA] • Dr Cesar Palerm [Medtronic]• Dr. Cesar Palerm [Medtronic]• Dr. Eyal Dassau• Matt Percival• Rachel Gillis [Eastman]• Dr Youqing Wang• Dr. Youqing Wang• Rebecca Harvey• Dr. Benyamin Grosman• Christian Ellingsen
ll bCollaborators: Lois Jovanovic (Sansum), Howard Zisser (Sansum), Dale Seborg (UCSB)