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Electronic Detection and Diagnosis of Health and Illness of Premature Infants. Co-Workers. Medical Folks Randall Moorman Pamela Griffin John Kattwinkel Alix Paget-Brown Brooke Vergales Kelley Zagols Andy Bowman Terri Smoot. Quants Statisticians Doug Lake George Stukenborg

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co workers
Co-Workers

Medical Folks

Randall Moorman

Pamela Griffin

John Kattwinkel

Alix Paget-Brown

Brooke Vergales

Kelley Zagols

Andy Bowman

Terri Smoot

Quants

Statisticians

Doug Lake

George Stukenborg

Chemical Engineers

John Hudson

Matthew Clark

Craig Rusin

Lauren Guin

Physicists

Abigail Flower

Hoshik Lee

John Delos

Supported by NIH.

overview
Overview

What can we Quants contribute?

Statistical measures

Signal Analysis

Pattern recognition methods

Dynamical theories

Medical Issues:

Apnea of Prematurity

Neonatal Sepsis

Observations:

Electronic Monitoring

of Heart, Respiration

slide4

Outline

Sepsis

medical issue

heart rate monitoring

statistical measures

randomized clinical trial

pattern recognition

physiological modeling

Apnea

medical issue

chest impedance – cardiac artifact

filtering, signal analysis

examples

future work

Conclusion

slide5

Sepsis

the presence of bacteria, virus, fungus, or other organism in the blood or other tissues and the toxins associated with the invasion.

Of 4 million births each year, 56,000 are VLBW (<1.5 Kg). For them the risk of sepsis is high (25-40%)

Significant mortality and morbidity (doubled risk of death in VLBW infants; increased length of NICU stay; high cost).

The diagnosis of neonatal sepsis is difficult, with a high rate of false negatives

Physicians administer antibiotics early and often.

Can heart rate monitoring give early warning of sepsis?(The invading organisms, or the immune response, may affect the pacemaking system.)

Randall Moorman

does heart rate give warning of illness plot time between beats vs beat number
Does heart rate give warning of illness?Plot (Time Between Beats) vs (Beat Number)

ms

ms

beat number

beat number

does heart rate give warning of illness plot time between beats vs beat number1
Does heart rate give warning of illness?Plot (Time Between Beats) vs (Beat Number)

Reduced variability

Repeated decelerations

pathologic

normal

vs.

pathologic

pathologic

expand

statistical measures of rr interval data
Statistical Measures of RR Interval Data
  • Standard Deviation and Sample Entropy: Variability in the signal.
  • Sample Asymmetry: Prevalence of decelerations over accelerations implies a skew, or asymmetry, in the data which we can detect statistically.
slide10

Find correlation of those measures with illness, and report correlation in terms of “fold increase of risk of sepsis”:

Take any random moment.

Examine a window of 24 hours (plus 18 hours or minus 6 hours) around that moment.

On average, 1.8% of the infants in our first study had a sepsis event within that 24 hour window.

If we report a “five-fold increase of risk of sepsis”, it means that about 10% of the infants showing those heart rate characteristics had a sepsis event within that 24 hour window.

slide11

Medical Predictive Science Corporation

has developed and is marketing a system for

Heart Rate Characteristics monitoring in the NICU.

A computer beside each NICU bed continuously collects ECG data, extracts times of R peaks,

tracks RR intervals, and provides the following

Heart Rate Observation (HeRO).

This system is installed in several NICUs in the US,

and a large randomized clinical trial has just been completed.

slide14

Conclusion 1:

New quantitative analysis of noninvasive, electronically-measured heart rate characteristics – standard deviation, asymmetry, and sample entropy –

provides an early noninvasive warning

of sepsis events.

slide15

Randomized Clinical Trial

8 Hospitals UVa, Wake Forest, UAl (birmingham), Vanderbilt, Umiami, Greenville SC, Palmer (Orlando) Penn State

Control

Save HeRO data

but do not display it

152 deaths/1489, 10.2%

133 deaths/757, 17.6%

Sample

Display HeRO Score

(but do not tell clinicians

what to do)

2989 VLBW (<1.5 Kg)

1513 ELBW (<1 Kg)

slide16

Randomized Clinical Trial

8 Hospitals UVa, Wake Forest, UAl (birmingham), Vanderbilt, Umiami, Greenville SC, Palmer (Orlando) Penn State

Control

Save HeRO data

but do not display it

152 deaths/1489, 10.2%

133 deaths/757, 17.6%

Sample

Display HeRO Score

(but do not tell clinicians

what to do)

122 deaths/1500, 8.1%

100 deaths/756, 13.2%

2989 VLBW

Δ = 2.1% absolute, 22% relative

1513 ELBW

Δ = 4.4% absolute, 33% relative

slide17

Conclusion 2:

New quantitative analysis of noninvasive, electronically-measured heart rate characteristics – standard deviation, asymmetry, and sample entropy –

saves lives.

slide18

New Question:

Would direct measures of decelerations

provide additional information?

pattern recognition for detecting decelerations abigail flower
Pattern Recognition

for detecting decelerations

Abigail Flower

slide25

Conclusion 2

Counting and measuring decelerations gives a second method for early warning of sepsis.

Also an important finding was that HR decelerations

are surprisingly similar in infants.

discovery
Discovery

We found that, within extended clusters of decelerations, there were sometimes shorter intervals of time, lasting up to several hours, in which the decelerations showed remarkable periodicity.

slide27

For six infants in our study population we identified deceleration clusters in which periodicity was maintained for at least ten minutes.

In these periodic bursts of decelerations, the time to the next deceleration was about 15 sec.

slide28

New Question:What Causes Periodic Decelerations?Can we develop a model capable of producing decelerations like those observed in neonatal HR records? Such models can guide future observations or experiments on animals.

slide29
Partial Answers

A. A mathematical model with minimal physiological assumptions: a noisy Hopf bifurcation

  • Physiologically-based models

The pacemaker?

The baroreflex loop?

Periodic apneas?

slide30
HR jumps from small fluctuations [“steady-state”] to periodic decelerations [above-threshold oscillations].
hopf bifurcations the most common way that a rest point changes to a cycle
Hopf Bifurcationsthe most common way that a rest point changes to a cycle

Hard (Subcritical) Hopf bifurcation:

small excerpt of real data and simulation
Small excerpt of real data and simulation.

large periodic decels

data

small periodic fluctuations

simulation

Hard Hopf oscillations

noise-induced subthreshold oscillations

slide37
Conclusion

Output of a Noisy Hopf Bifurcation Model

Resembles

Observed Periodic Decelerations

Thus we have a mathematical model with minimal physiological assumptions: a noisy Hopf bifurcation.

Is there a physiologically-based model?

slide38

Pacemaker cells

  • Sino-Atrial node cells are the natural pacemaker of the heart. Can they go into “FM” mode with period ~15 seconds?
  • Baroreflex loop
  • The feedback loop connecting blood pressure and heart rate can go into oscillation with period ~14 seconds in infants. Does this resemble the observations?
  • Periodic apneas
  • Apneas produce decelerations of the heart. Sometimes they occur periodically, and the period is commonly ~15 seconds.
slide39

Mayer (low freq) arrhythmia

RR

HR

BP

BP

                  • Oscillation with period ~14 s in infants.
  • Feedback loop with time delay.
  • Many models connect Mayer waves with a Hopf bifurcation.
  • However, measurements indicate that under physiological conditions in adults, the feedback loop is stable (no oscillations)
  • Two studies (DeBoer et al. and Chapuis et al.) propose that observed Mayer waves are noise-driven subthreshold oscillations
hypothesis noisy precursors are familiar mayer waves
Hypothesis: Noisy Precursors are Familiar Mayer Waves.

There MUST be a nearby threshold.

Decelerations are result of a parameter

going above the bifurcation.

slide41

Rate of change of = Rate in from heart –

blood volume in arteries Rate out through capillaries to veins

dV / dt = heart rate x blood volume per beat 

- [P(arteries) - P(veins) ] / [Resistance]

P(arteries) = V(arteries) / [compliance = ]

Similar formulas for veins

Rate of change of = Neg(t) a negative term caused by high BP

heart rate + Pos(t -τ ) a positive term caused by low BP

which however is delayed

A model of the baroreflex loop

J. Ottesen, Roskilde University, Denmark

slide42

A problem in nonlinear dynamics

Do these differential equations have a bifurcation that causes heart rate and blood pressure to oscillate?

slide43

A problem in nonlinear dynamics

Do these differential equations have a bifurcation that causes heart rate and blood pressure to oscillate?

YES!!

What is the period ??

slide44

A problem in nonlinear dynamics

Do these differential equations have a bifurcation that causes heart rate and blood pressure to oscillate?

YES!!

What is the period ??

Depending on parameters, can be ~ 15 seconds.

Do they resemble the observed oscillations?

slide45

A problem in nonlinear dynamics

Do these differential equations have a bifurcation that causes heart rate and blood pressure to oscillate?

YES!!

What is the period ??

Depending on parameters, can be ~ 15 seconds.

Do they resemble the observed oscillations?

Nope.

Do measurements of HR and BP in infants show the large correlated oscillations?

slide46

A problem in nonlinear dynamics

Do these differential equations have a bifurcation that causes heart rate and blood pressure to oscillate?

YES!!

What is the period ??

Depending on parameters, can be ~ 15 seconds.

Do they resemble the observed oscillations?

Nope.

Do measurements of HR and BP in infants show the large correlated oscillations?

Nope.

slide47

The Future: Incoming Data Streams

  • 1. Electronic diagnosis of infectious disease? Can we identify invading organisms by HR monitoring?
  • Preliminary evidence:
  • Reduced variability Gram-positive bacteria (e.g. Streptococci, Staphylococci)
  • vancomycin
  • Clusters of decels Gram-negative bacteria (e.g. E. coli, Pseudomonas)
  • gentamicin, cefotaxime
  • If this preliminary result holds up, we have the first example of continuous, noninvasive, purely electronic monitoring that gives early warning of infectious disease and also gives partial diagnosis, thereby identifying the recommended therapy.
  • (A medical tricorder)
slide48

The Future: Experiments proposed or discussed

2. Quadriplegics are subject to

infections that they do not feel.

Can heart rate monitoring

provide early warning?

3. Can large decelerations be induced in animals?

Models suggest that increasing the time delay in the baroreflex loop pushes the system above bifurcation.

Can this be done by chemical means (beta blockers)?

Or electrical means (cut the sympathetic nerve

and use an electrical time delay circuit)?

What happens when corresponding experiments are done on newborn or premature animals?

slide51
Conclusions
  • Decelerations are correlated with illness, and can be used as a new, noninvasive monitor for illness of premature infants.
  • Periodic decelerations resemble the output of a model based on Hopf bifurcation theory.
  • Study of periodic apneas is the next step.
  • The search for corresponding phenomena in animals has clinical, developmental, and dynamical significance.

5. When we quants work together with physicians, and overcome the knowledge barrier and communication barriers between us, important and unexpected advances in health care can be made.

apnea of prematurity aop
Apnea of Prematurity (AOP)

Apnea(cessation of breathing) is very common for premature infants.

  • > half of babies whose birth weight < 1500 g (VLBW)
  • Almost all babies whose birth weight < 1000 g (ELBW)

Definition of (clinical) AOP

Cessation of breathing > 20s OR

Cessation of breathing > 10s + Bradycardia (Heart Rate < 100 bpm) or O2 Desaturation (SpO2 < 80%)

and

VLBW : Very Low Birth Weight, < 1500g

ELBW : Extremely Low Birth Weight, < 1000g

slide53

Three types of apnea are common in premature infants.

  • Obstructive apnea : a blockage of the airway, typically accompanied by struggling or thrashing movements of the infant.
  • Central apnea : cessation of respiratory drive, and the infant makes no effort to breathe.
  • Mixed apneas : obstructive central.

Central apnea is taken to indicate immaturity of control of respiration, and discharge from UVaNICU is delayed until apneas have been absent for 8 days.

Apnea may be cause or an effect of many other clinical illnesses including sepsis or abnormal neurologic development. It is a serious clinical event which needs immediate medical attention.

However, the current generation of apnea monitors is unsatisfactory.

data collection
Data Collection
  • Since January 2009, we have collected all waveform and vital sign data from the bedside electronic monitors in the UVa NICU.
    • Waveforms: ECG, Chest Impedance, Pulse Ox
    • Vital signs: Heart & respiration rates, oxygen saturation of hemoglobin
    • ~ 1 TB / Baby-Year
  • About 1300 admissions for over two years, more than 300 VLBW infants.
  • Monitor alarms are stored (e.g. brady, desat, and apnea etc..).
  • Clinical data relevant to respiratory support are entered manually into an connected clinical database, including presence and type of ventilatory support such as mechanical ventilation.
  • Administration of medication (e.g. caffeine)
chest impedance measurement
Chest Impedance Measurement
  • Easiest way to monitor the respiration of baby
  • Impedance between two electrodes placed at
  • the chest.
  • Use two electrodes already in use for the
  • measurement of the EKG signal, but use a
  • frequency (52 kHz) far outside the EKG signal.
  • Basic impedance (static) : several hundred ohms: muscles, tissue, blood + electrode-skin transitions, and wires.
  • Respiration : ~ 2 ohm
  • - Air has poor conductivity
  • - More air in the lung, higher impedance
  • Heart activity : ~ 0.5 ohm
  • - Blood is more conductive than air
  • - Pumping blood out of thorax, less impedance
slide56

200

100

200

100

0

Heart Rate

ECG

Chest Impedance

Respiration Rate

ECG & Chest Impedance

slide57

200

100

200

100

0

Heart Rate

ECG

Chest Impedance

Respiration Rate

ECG & Chest Impedance during Apnea event

slide58

200

100

200

100

0

Heart Rate

ECG

Chest Impedance

Respiration Rate

ECG & Chest Impedance during Apnea event

slide59

How do we remove the cardiac artifact from chest impedance signal?

Filtering, signal analysis, pattern recognition

Hoshik Lee

slide60

Goal :

  • Filter the heart signal from chest impedance.
  • Simple Fourier filter fails. Heart beat band is too broad. Especially, the heart beat slows during apnea.

Fourier Transform of

chest impedance

Use the Heart as the Clock !

Cardiac artifact in chest impedance

contract/stretch

RR intervals are evenly spaced.

Heart Clock

1RR

1RR

slide61

Goal :

  • Filter the heart signal from chest impedance.
  • Simple Fourier filter fails. Heart beat band is too broad. Especially, the heart beat slows during apnea.

Fourier Transform of

chest impedance

Use the Heart as the Clock !

Cardiac artifact in chest impedance

contract/stretch

RR intervals are evenly spaced.

Heart Clock

1RR

1RR

slide62

Goal :

  • Filter the heart signal from chest impedance.
  • Simple Fourier filter fails. Heart beat band is too broad. Especially, the heart beat slows during apnea.

Fourier Transform of

chest impedance

Use the Heart as the Clock !

Cardiac artifact in chest impedance

contract/stretch

RR intervals are evenly spaced.

Heart Clock

1RR

1RR

slide63

Fourier Transform of CI

Fourier Transform of CI

Using Heart Clock

slide64

Fourier Transform of CI

Fourier Transform of CI

Using Heart Clock

Cardiac Artifact

slide65

Fourier Transform of CI

Fourier Transform of CI

Using Heart Clock

Cardiac Artifact

Breathing

slide66

Fourier Transform of CI

Fourier Transform of CI

Using Heart Clock

Cardiac Artifact

Slow change : movement or unknown but not breathing

Breathing

slide67

`

HR

EKG

Chest Impedance

Chest impedance

Cardiac Artifact Removed

Filtered

Chest Impedance

There remain some small fluctuations in filtered CI. Compute the residual variance of the signal on 2 sec intervals, spaced by ¼ sec, and get a probability of apnea.

slide68

Probability of Apnea

‘Energy’ in fluctuations (variance)

slide69

Probability of Apnea

‘Energy’ in fluctuations (variance)

Thresholding function looks like the Fermi distribution function. We obtain fitting function with two parameters.

slide70

Summary: from Chest impedance to probability of apnea

CI

Remove cardiac artifact

Remove slow variations and renormalize

Compute

2s variance

P(apnea)

slide71

Examples

Philips Research North America 07/13/2011

very long apnea undetected by monitor
Very Long Apnea Undetected by monitor

We detected 782 apneas > 60 s in two years data

slide74

Periodic Breathing = Periodic Apneas

1

0

Philips Research North America 07/13/2011

200

100

100

100

50

0

slide75

Current Studies

  • What fraction of apneas are recorded by nurses? (~1/3)
  • How does the apnea rate change with age? ^
  • Does caffeine reduce apnea? (?)
  • Do transfusions reduce apnea? (Yes)
  • Can we get early warning of serious apneas? (Maybe)
  • What is the significance of long apneas?
  • Are short but periodic apneas benign?
  • Future Work
  • Convert to real-time monitor
  • -The system is set up for retrospective work : collecting statistics of apnea events and correlation with other clinical events.
  • Combined with (wearable) Automatic Stimulation system.
  • - e.g. vibrate shirt, mattress and so on.
  • Improve sepsis detection? (HeRO monitoring)
  • Add-on system which provides a new way to analyze data
  • that had previously been discarded
slide78
Conclusions
  • Decelerations are correlated with illness, and can be used as a new, noninvasive monitor for illness of premature infants.
  • Periodic decelerations resemble the output of a model based on Hopf bifurcation theory.
  • Study of periodic apneas is the next step.
  • The search for corresponding phenomena in animals has clinical, developmental, and dynamical significance.

5. When we quants work together with physicians, and overcome the knowledge barrier and communication barriers between us, important and unexpected advances in health care can be made.

slide83
ASSUME:

the heart rate is governed by some set of feedback loops that can be modeled by some big set of differential equations

dx/dt = F(x;p)

x = (x1,x2,…) (dynamical variables)

p = (p1,p2,…) (parameters)

Example:

x1 = heart rate, x2 = blood pressure, x3 = …

slide84

The equations have a “rest point” at which

  • all variables are constant (including HR)
  • F(xrest(p);p) = 0.
  • Move origin of coordinates so rest point = 0.
  • F(x;p) can be expanded in a Taylor series
  • in x’s.
  • F(x;p) = Mx + xNx +….
  • Analyze first at linear level.
slide85

Almost all matrices can be transformed to diagonal form

At linear level

Equations are real, so eigenvalues are real

or come in complex conjugate pairs

slide86

All except two eigenvalues have negative

  • real parts. Two eigenvalues are complex,
  • and have real part near zero.

is near zero, and as parameters p change, it can pass through zero.

THEN:

slide87

[Center Manifold Theorem]

  • In the many-dimensional y-space, there is a
  • smooth two-dimensional surface called the
  • center manifold, in which all the interesting
  • behavior occurs:
  • If the system starts on that surface, it
  • stays on that surface
  • b. If it starts elsewhere, it decays to that
  • surface
  • The equations in that surface have a
  • Taylor expansion
slide88

AND FURTHERMORE:

[Normal Form Theorem]

There exists a smooth change of coordinates

such that the diff eqs can be put into a “Normal

Form”; using polar coords in the center

manifold, that form is:

and this is easy to analyze !!!!

slide89

YOU can easily show:

As increases through zero,

The stable rest point goes unstable, and

EITHER

A stable cycle appears

OR

An unstable cycle disappears

That is a Hopf bifurcation.

slide90

Summary: In the many-dimensional space, there is a smooth two-dimensional attractor in which all the interesting behavior occurs, and there exists a smooth change of coordinates such that the diff eqs can be put into a “Normal Form”:

As increases through zero, the stable rest point goes unstable, and either a stable cycle appears,

or an unstable cycle disappears

That is a Hopf bifurcation.

slide92

In the new variables the motion is a sinusoidal oscillation,

We can connect to time between beats RR(t)

by assuming RR = RR(u(t)) = RR(r cos ).

But we know the shape of the decelerations, and we can represent that shape by a Fourier cosine series.

Then the sinusoidal oscillation is converted into a sequence of decelerations.

slide94

Small time delay

Heart rate

Arterial BP

Venous BP

slide95

These oscillations are “noisy precursors” :

With no noise the system goes to steady state

Subthreshold oscillations arise because of noise and a nearby bifurcation

slide96

Peter Andriessen

High freq fluctuations: RR ~ opposite to BP respiratory arrythmia

Low freq fluctuations: BP leads RR Mayer waves

slide97

Above the bifurcation (longer time delay)

the system oscillates even with no noise.

slide98

Above bif, the oscillations are large. The shape is (maybe) a passable imitation of periodic decels seen in infants. Period 10 s for adults.

RR

time

slide100

Comparison of model (based on adult data) with observations:

  • There is a bifurcation which produces large regular oscillations in HR. Increase in delay time of sympathetic action gives the bif.
  • Shape of decels – could be better.
  • Liapunov exponent is too small. (Slow approach to steady oscillations.)
  • It’s a soft Hopfbif instead of a hard Hopfbif.
  • (I think by playing with parameters we might convert it to hard Hopf.)
  • Continuing research:
  • More fun with baroreflex models
  • Begin study of respiration models
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