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An Overview of the Archimedes

Healthcare Model

The Archimedes Project


Kaiser Permanente

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This presentation will address
three main topics:

• What the Archimedes model is


• How it can be used
• How we know it works

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Until now, there have been four main kinds
of mathematical models in health care
• Biological modeling
– e.g. glucose metabolism, Starling heart equation
• Clinical Medicine
– e.g. Regression equations, Markov models
• Operations research / management science
– e.g. Schedule operating rooms, plan hospitals
• Economic / system resources
– e.g. Forecasting
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Archimedes is a new type of
mathematical model of health care:
it includes all four components
Biological modeling

Clinical medicine

Care processes

System resources

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Archimedes is also new
because it is anchored to reality
through clinical trials

Biological modeling

Clinical medicine

Care processes

System resources

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This presentation will address four
main topics. Let’s begin with:
• What the Archimedes model is
• How it can be used
• How we know it works
• What we plan to do with it
• How you will be able to get access to it
• What’s on this website

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Archimedes is

• Object oriented
• Continuous
• Physiology based
• Very deep and very broad
• and it operates at the level of detail that
clinicians and administrators consider essential
for making decisions

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Now let’s define those terms. This is
what we mean by “object oriented”
• All the important objects in reality have
corresponding objects in the model, one-to-one,
at a high level of detail

ƒ Patients, organs, parts ƒ Equipment, supplies


of organs
ƒ Policies and procedures
ƒ Facilities
ƒ Budgets, regulations,
ƒ Health care personnel more

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More specifically, this means that
• There are thousands of simulated people in the
model, each one of them different
• They can get sick, and go see simulated doctors
• In simulated offices
• And get simulated tests, that use simulated
pieces of equipment
• And get simulated treatments
• And so forth
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This is what we mean by “continuous”

• Biological variables that are continuous in


reality are continuous in the model (e.g. BP,
LDL cholesterol)
– No “clinical states”, “strata”
• Time is continuous; any event can occur at any
time
– No “ticks”, “steps” or “annual jumps”

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The concept of “physiology based”
needs more explanation. And we’re
going to need a volunteer
I’ll
volunteer
Thanks. What’s
your name?

Joe.
Joe Miner
OK Joe.
I hope you’re not
ticklish…

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… because we’re going
to need to look inside
your belly.
Can you come a bit
closer?
Sure

A little bit closer,


if you can

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How’s
this?

That’s good.
Nice belly, Joe.
Now we’re going to need to
do a sort of x-ray
OK.
The reason we’re
doing this is that we
want to show you that
every simulated
person in the model,
like Joe, has organs,
such as…
Heart

And every organ has all of its


Liver types of cells, like these beta
cells of the pancreas

Pancreas
Circulatory
system

Fat cells
Gut Muscle
The organs and
their cells carry out
metabolic
functions,
such as…
GLYCOGEN
GLYCOGEN CIRCULATING
HEPATIC GLUCOSE
GLUCOSE
GLUCOSE
GLUCOSE
PRODUCTION

GLUCOSE
UPTAKE BY
MUSCLE
GLUCOSE SUGARS
UPTAKE
BY FAT
In the model, these
functions are regulated just
as they are in a real person.
For example, in response to
the circulating levels of
glucose, the pancreatic beta
cells will secrete insulin
GLYCOGEN CIRCULATING
HEPATIC GLUCOSE
GLUCOSE GLUCOSE INSULIN
PRODUCTION

GLUCOSE
UPTAKE BY
MUSCLE
GLUCOSE SUGARS
UPTAKE
BY FAT
And diseases can occur.
For example, in a person
with diabetes the effect of
insulin on uptake of
glucose by the muscle
and fat is decreased.
GLYCOGEN

HEPATIC
GLUCOSE GLUCOSE INSULIN
PRODUCTION

Diabetes

GLUCOSE
UPTAKE BY
MUSCLE
GLUCOSE SUGARS
UPTAKE
BY FAT

Diabetes
Diabetes also affects the
effect of insulin on
production of glucose by
the liver cells
GLYCOGEN
Diabetes
HEPATIC
GLUCOSE GLUCOSE INSULIN
PRODUCTION

GLUCOSE
UPTAKE BY
MUSCLE
GLUCOSE SUGARS
UPTAKE
BY FAT
If we were to illustrate the
biological variables and
relationships in the model
that affect the metabolism
of glucose, it would look
something like this
Unexplained
Family Insulin OGT OGTT test
Gliburide Insulin level variance in
history treatment
OGT

Random Random
Diabetes
plasma plasma
Sex diagnosis
glucose glucose test
Type 1 Insulin
Diabetes production
feature Joint (Pancreas) Glucose
Race/ uptake by Random FPG test
Diabetes
ethnicity muscle error and
Type 2 feature
Insulin variation
Diabetes efficiency FPG
feature (Muscle) Glucose HbA1c test
Age production
Insulin by liver
efficiency Untreated Care Urine
Age, sex, (Liver) insulin level processes ketone test
BMI race/ Normal liver To
ethnicity glucose treatment
production Fractional models
Keto-
Metformin change in
acidosis
Insulin

Height Weight
Diet and Hypo-
FPG
exercise glycemia
Patient
Diabetes takes action
Diabetes Propensity
blood HDL LDL Triglyceride Blurred
Smoking cardiac risk to blurred
pressure cholesterol cholesterol s vision
factor vision
factor
Memory
Mean Systolic Coronary
Peripheral Propensity
arterial blood artery Polyuria
resistance to polyuria
pressure pressure stenosis FPG
Perception

Cardiac Arterial Pulse \ Propensity


Fatigue
output compliance pressure to fatigue

To the
To the To the To the Coronary
Propensity
Retinopathy Nephropath Neuropathy artery Thirst
to thirst
model y model model disease
model A KAISER PERMANENTE INNOVATION
All of that, and
many, many
more variables
that are important
to the
complications of
diabetes and to
other diseases, Family
history
Gliburide
Insulin
treatment
Insulin level
Unexplained
variance in
OGT
OGT

Random
OGTT test

Random
plasma
Diabetes
plasma

are being
Sex diagnosis
glucose glucose test
Type 1 Insulin
Diabetes production
feature Joint (Pancreas) Glucose
Race/ uptake by Random FPG test
Diabetes
ethnicity muscle error and
Type 2 feature
Insulin variation
Diabetes efficiency FPG
feature (Muscle) Glucose HbA1c test
Age

calculated
production
Insulin by liver
efficiency Untreated Care Urine
Age, sex, (Liver) insulin level processes ketone test
BMI race/ Normal liver To
ethnicity glucose treatment
production Fractional models
Keto-
Metformin change in
UKPDS acidosis
Insulin

continuously in
data
Height Weight
Diet and Hypo-
FPG
exercise glycemia
Patient
Diabetes takes action
Diabetes Propensity
blood HDL LDL Triglyceride Blurred
Smoking cardiac risk to blurred
pressure cholesterol cholesterol s vision
factor vision
factor

every simulated
Memory
Mean Systolic Coronary
Peripheral Propensity
arterial blood artery Polyuria
resistance to polyuria
pressure pressure stenosis FPG
Perception

Cardiac Arterial Pulse \ Propensity


Fatigue
output compliance pressure to fatigue

person in the
To the
To the To the To the Coronary
Propensity
Retinopathy Nephropath Neuropathy artery Thirst
to thirst
model y model model disease
model

model

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And there are lots of
simulated people,
thousands in fact,
all of them with
different risk factors,
physiologies,
behaviors, et cetera.
(The differences are shown
as different colors of their
aprons)

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Thanks Joe, you
can go back to the You’re
model now. welcome.
Good bye

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That was “physiology-based”.
Let’s move on now.
Here’s what we mean by “broad and deep”
• Object oriented
• Continuous
• Physiology based
• Very deep and very broad
• and it operates at the level of detail that
clinicians and administrators consider essential
for making decisions
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“Very broad and very deep ” means
that the model includes
• Not only
– Anatomy, Physiology, Pathology, Signs and
symptoms, Tests and treatments
• But also
– Patient and provider behaviors
– Care processes: e.g. guidelines, disease
management, CQI
– System resources: e.g. facilities, personnel,
equipment, supplies, costs …
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To get the idea of “very deep and very
broad”, let’s follow a problem from the
cellular level to the parking lot
• All the simulated people in the model have all the
important organs. E.g. hearts, kidneys, immune
systems…
• All the simulated organs have all the important parts.
E.g. hearts have coronary arteries, ventricles,
myocardium, sino-atrial node…
• All the part have all the important subparts. e.g.
arteries have lumens, walls…
• All the organs and their parts have functions. e.g.
arteries carry blood to the myocardium
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There’s more
• Things can go wrong with the organs or their
functions. e.g. coronary arteries can occlude.
• When something goes wrong, it affects other
things. e.g. when arteries occlude, blood flow to
the myocardium is reduced. When blood flow is
reduced, the feels pain (angina).
• All the simulated patients have behaviors; when
the pain reaches a threshold, the patient makes a
simulated call to a simulated hospital.
• Simulated telephone operators at simulated call
centers use simulated protocols to triage calls.
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And still more
• Patients go to simulated emergency
departments. (This is where the parking lot
comes in)
• They are seen by simulated personnel (e.g.,
nurses).
• Simulated tests are performed…tests use
equipment and supplies
• Diagnoses are made…and mistakes are
made
• Patients are admitted, rooms are occupied, …
• Treatments are given…
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You get the idea. “Very broad” and
“very deep” means that the effects of
any encounter keep ramifying through
the simulated health care system,
just as happens in the real world
• Logistics happen…
• Utilization occurs…
• Outcomes occur…
• Costs occur…
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There’s one more thing to discuss,
the level of detail
• Object oriented
• Continuous
• Physiology based
• Very deep and very broad
• It operates at the level of detail that
clinicians and administrators consider
essential for making decisions
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The level of detail is determined by
the people who will use the model
• If a clinician says that a particular variable is
critical to their own thinking, and the model won’t
be credible without it …
• We include the variable
– e.g. ejection fraction, insulin level, “beta cell
fatigue”, peripheral resistance
• Ditto for administrators
– E.g. there are 37 different types of office visits
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Now let’s talk about:
• What the Archimedes model is
• How it can be used
• How we know it works

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The purpose of Archimedes is to
create a virtual world
• Virtual people
• who have virtual physiologies
• get virtual diseases
• have virtual signs and symptoms
• go to virtual doctors
• get virtual tests and treatments
• and have virtual outcomes
• just like real people
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If it works, then we can use the virtual world
to try out, evaluate, explore, optimize, plan,
improve, predict…lots of different things.
Such as…
• Guidelines
• Disease management programs
• Nursing algorithms
• Changes in care processes
• Continuous quality improvement programs
• Performance measures and targets
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And more…

• Priority setting
• Strategic goals
• Research
• How “ideal” research trials translate to
“real” clinical settings
• Logistics, use of resources
• Costs, cost-effectiveness, and value
• Planning
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The idea is that we can use the virtual world to
learn the effects of lots of different types of
interventions that would be infeasible to study
through empirical methods (more research), for a
variety of reasons:
• Too high a cost
• Too long time needed for a new study
• Too many patients needed
• Unwillingness of patients and/or physicians to
participate
• Too large a number of options to study
• Technologies that are changing too rapidly
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This is very important, because

• An empirical study – e.g. an evaluation study or


clinical trial – of a single intervention will
– cost hundreds of thousands, or even
hundreds of millions of dollars
– require hundreds, or thousands of people
– take years
• Whereas an Archimedes simulation takes much
less time and costs less

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Sounds good. And I’m happy
to help out. But if you don’t
mind, I’ve got a question.
All this is premised on an
assumption that it works
right. How do you know that
it works?

I mean, I know
that my
equations are
working fine. But
I’m not so certain
about the other
jokers who are in
here with me.

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Thanks Joe, that is indeed a
crucial question:
• What the Archimedes model is
• How it can be used
• How do we know it works?

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Here’s how:
• We compare what happens in the virtual
world with what happens in the real world,
• in lot’s of different settings,
• that test the parts of the model that will be
used for the types of applications we want
to do
– i.e. similar people, similar treatments, similar
outcomes
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The best way to do this is to use
clinical trials because we know the
most about them
A trial involves people
who meet the entry
criteria for the trial

The trial is And the


conducted outcomes are
measured
They get the treatments
specified in the
protocols of the trial
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We use the virtual world of the model to
simulate the real-world trial
People
Real clinical Real
trial Outcomes
Treatments

And we compare the results


We use the
same criteria to
We count the
select people We let the model outcomes, using
do its thing the same
We have simulated
physicians follow definitions and
the same treatment protocols
protocols A KAISER PERMANENTE INNOVATION
There are 10 steps involved in
performing a validation
1. We start with a large population of
simulated people, just like a simulated city
2. We identify the inclusion criteria for the trial
3. We randomly select from the large
population a sample who meet the inclusion
criteria for the trial
4. Confirm that major characteristics match
(“Table 1”)
5. Randomize the simulated people
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There are 10 steps involved in
performing a validation (Cont’d)
6. Identify the treatment protocols used in the
trial
7. Have simulated providers apply the
treatment protocols to the simulated people
8. Have the simulated providers apply the
follow-up protocols
9. Record the results seen in the real trial
10. Compare the simulated results to the real
results
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You can think of these validations as
being previews of real applications
• We used the populations that were in the
trials
– But we could have used the population that
would be candidates for your guideline (or
performance measure, etc)

• Similarly for the tests, treatments,


outcomes, etc.
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Archimedes has been validated
against these trials, so far
MRC HOPE DCCT primary
SHEP 4-S DCCT secondary
HHS CARE MICRO-HOPE
LLRC LIPID IRMA
WOSCOPS DPP Lewis
HPS UKPDS IDNT
VA-HIT
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Here’s an example: the Heart
protection Study

• Population: adults age 40 – 80, at high risk


of MI because of high LDL, or other
arterial occlusive disease, or diabetes
• Treatments: Simvastatin vs. placebo
• Size: 20,500
• Duration: 6 years
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This was the rate of major coronary artery
events in the placebo and treated groups
Major Coronary Events in Heart Protection Study
0.14
Solid lines are the real results
0.12

0.1
Fraction of patients

Placebo group
0.08

0.06

Treated group
0.04

0.02

0
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Years
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The dotted lines showed what the
model calculated
Major Coronary Events in Heart Protection Study
0.14
Dotted lines are the model’s results
0.12

0.1
Fraction of patients

Placebo group
0.08

0.06
Treated group
0.04

0.02

0
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Years
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Here’s another example, the Diabetes
Prevention Program
• Population: men and women over age 25.
broad range of racial and ethnic groups.
Prediabetes (IGT or IFG)
• Treatments: intensive lifestyle vs.
Metformin vs. standard care
• Size: 3000
• Mean duration: 2.8 years
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In this case, the results were calculated by
the model before the real results were
known. This is what the model predicted.
DPP: Diabetes Progression
0.5

0.45 Control
0.4 Metformin
0.35
Lifestyle
0.3
Fraction

0.25

0.2

0.15

0.1

0.05

0
0 1 2 3 4 5
Time (years)

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The dotted lines are what the model
predicted. The solid lines are the results
that were eventually published.
DPP: Diabetes Progression
0.5

0.45 Control
0.4
Metformin
0.35
Lifestyle
0.3
Fraction

0.25

0.2

0.15

0.1

0.05

0
0 1 2 3 4 5
Time (years)

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Here’s an example of a long term trial that
measured the effects of treatment on
complications of diabetes: UKPDS
• Population: middle aged men and women, with
newly diagnosed type 2 diabetes
• Treatments: intensive treatment vs. conventional
treatment
• Size: 3900
• Duration: 15 years

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This shows the effect of treatment on the
most important outcome: heart attacks
UKPDS: MI (fatal and non-fatal)
0.3

The solid lines are the real results


0.25
Conventional
treatment
Fraction of patients

0.2

0.15

Intensive
0.1 treatment

0.05

0
0 2 4 6 8 10 12 14
Time (years)
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This is what was calculated by the model
UKPDS: MI (fatal and non-fatal)
0.3
The dotted lines are the model’s results
0.25
Conventional
treatment
Fraction of patients

0.2

0.15

Intensive
0.1
treatment

0.05

0
0 2 4 6 8 10 12 14
Time (years)
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We have done this for 74 different combinations
of populations, treatments and outcomes. This
chart compares results calculated by the model
(y-axis) against results of the real trial (x-axis).
0.6
Each dot represents
an arm of a trial. The
Results calculated by model

0.5

real result of the trial is


0.4
plotted against the
0.3
result calculated by
the model. Perfect
0.2 correspondence would
be the 45º line
0.1

0
0 0.1 0.2 0.3 0.4 0.5 0.6
Results from trials
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One would not expect perfect
correspondence because of random factors,
related to the number of people in the trial
• 71 of 74 are well within sampling error
• The other 3 have good explanations
– either it just missed (e.g. p = .04) (which is to
be expected statistically)
– or the description of the trial was incomplete
• 54 of 74 are within ± 1 standard deviation
• For all 74 exercises: r = 0.99
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For some of the trials, some of the data
from the trial were used to help build
parts of the model. The other trials are
100% independent
• For the exercises that were not used at all to
build the model (100% independent), the
correlation between the model and the trial was
still extremely high
• The correlation was still r = 0.99

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These validations are important for
several reasons
• They give us confidence that for applications
that are spanned by validations, the model is
accurate
• They illustrate the types of applications that
the model can do
• No other model of clinical medicine has been
validated in this way
• The alternative to the model, expert judgment,
has not been validated in this way either (no
offense intended) A KAISER PERMANENTE INNOVATION
The “span” of the validations is important,
because it indicates the types of populations,
organ systems, and treatments we can be
confident about

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Imagine that the disease that we want to
understand is represented by an island.
We need to completely map out and reach every
part of that island

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Imagine that the available research can be
represented as radio beacons on the island.
The bigger and better the trial, the wider its signal.

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Now suppose that Archimedes has been
validated against all of those trials.
Using this visual image, we can talk about the
usefulness of Archimedes for new applications

A KAISER PERMANENTE INNOVATION


If you ask it a question about this part of the
island (A), it should do extremely well

A KAISER PERMANENTE INNOVATION


If you ask it a question about this part of the
island (B), it should do very well

A KAISER PERMANENTE INNOVATION


If you ask it a question about this part of the
island (C), it should do fairly well

A KAISER PERMANENTE INNOVATION


If you ask it a question about this part of the
island (C), it should do fairly well,
but we’d like to see a new trial done down here

A KAISER PERMANENTE INNOVATION


If you ask it a question about this part of the
island (D), we’ll say “OK, but only use the
model for “what if” type questions
We’d rather help you design a new trial

A KAISER PERMANENTE INNOVATION


If you ask it a question about that is out in
the ocean (E), We’ll say “Archimedes can’t
do that yet. Help us raise some money and
we’ll build a new model for that”

A KAISER PERMANENTE INNOVATION


With that in mind, it is important that
Archimedes has been validated for a wide
range of populations
ƒ Average risk ƒ Newly diagnosed diabetes
ƒ Hypercholesterolemia ƒ Type 1, uncomplicated
ƒ Diastolic hypertension ƒ Type 1, retinopathy
ƒ Systolic hypertension ƒ Type 1, moderate to
ƒ Many risk factors severe nephropathy
ƒ Angina or MI ƒ Type 2, uncomplicated
ƒ Diabetes ƒ Type 2, mild nephropathy
ƒ MI average Cholesterol ƒ Type 2, moderate
ƒ MI high Cholesterol nephropathy
ƒ Pre diabetes ƒ Young, Middle age, Old
A KAISER PERMANENTE INNOVATION
…and organ systems

• Liver • Muscle
• Pancreas • Fat
• Heart • Kidneys
• Vascular • Eyes
• Nerves • Lungs
• Gut

A KAISER PERMANENTE INNOVATION


…and treatments

• Nothing (placebo) • Angiotensin –II-


• Cholestyramine receptor antagonists
• Gemfibrozil • Insulin
• Anti-hypertensive • Metformin
• Pravastatin • Sulphonylurea
• Simvastatin • General diet advice
• ACE Inhibitors • Intensive lifestyle

A KAISER PERMANENTE INNOVATION


That’s what we mean when we say that
Archimedes is anchored to reality

Biological modeling

Clinical medicine

Care processes (74 anchors)

System resources

A KAISER PERMANENTE INNOVATION


What does all this mean?

• It is possible to write equations that represent


human physiology, disease, treatments and
outcomes using existing information
• In the “virtual world” created by these
equations, simulated patients behave like
patients in the real world, …
• …at least as we know it through the most
important epidemiological studies and clinical
trials

A KAISER PERMANENTE INNOVATION


It means the virtual world can be
used for many purposes, such as
• Guidelines
• Performance measures
• Disease management programs
• Continuous quality improvement
• Strategic goals and priority setting
• Research planning
• Estimating patient-specific outcomes
A KAISER PERMANENTE INNOVATION
And that’s good, because it’s a whole
lot easier to explore problems and
programs in the virtual world
• Much faster
• Much less expensive
• Much more flexible
• Can explore many more options
• Can tell you the critical points to watch
A KAISER PERMANENTE INNOVATION
If you want to use the model, there is one
more thing you will need to understand
• Real people like you will still have to make the
final decisions
• Archimedes will give you much better
information than you’ve ever had before
• But there are always elements of a decision that
can not be quantified and that require value
judgments
• This is the role of humans
• Thus the model is a just a tool -- a very powerful
tool, but just a tool
A KAISER PERMANENTE INNOVATION
But watch
out. I’m
gaining on
you.

Unexplained
Family Insulin OGT OGTT test
Gliburide Insulin level variance in
history treatment
OGT

Random Random
Diabetes
plasma plasma
Sex diagnosis
glucose glucose test
Type 1 Insulin
Diabetes production
feature Joint (Pancreas) Glucose
Race/ uptake by Random FPG test
Diabetes
ethnicity muscle error and
Type 2 feature
Insulin variation
Diabetes efficiency FPG
feature (Muscle) Glucose HbA1c test
Age production
Insulin by liver
efficiency Untreated Care Urine
Age, sex, (Liver) insulin level processes ketone test
BMI race/ Normal liver To
ethnicity glucose treatment
production Fractional models
Keto-
Metformin change in
UKPDS acidosis
Insulin
data
Height Weight
Diet and Hypo-
FPG
exercise glycemia
Patient
Diabetes takes action
Diabetes Propensity
blood HDL LDL Triglyceride Blurred
Smoking cardiac risk to blurred
pressure cholesterol cholesterol s vision
factor vision
factor
Memory
Mean Systolic Coronary
Peripheral Propensity
arterial blood artery Polyuria
resistance to polyuria
pressure pressure stenosis FPG
Perception

Cardiac Arterial Pulse \ Propensity


Fatigue
output compliance pressure to fatigue

To the
To the To the To the Coronary
Propensity
Retinopathy Nephropath Neuropathy artery Thirst
to thirst
model y model model disease
model

A KAISER PERMANENTE INNOVATION