pro/con debate: pro to fev1 or not
TRANSCRIPT
Ron Dandurand, MD
Respiratory Effectiveness Group Summit
Lyon, France
April 15, 2016
Objectives
Objectives Prove non-inferiority of spirometry
Objectives Prove non-inferiority of spirometry
Raise reasonable doubt that spirometry ought to be abandoned at this point in time
Objectives Prove non-inferiority of spirometry
Raise reasonable doubt that spirometry ought to be abandoned at this point in time
Objectives Prove non-inferiority of spirometry
Raise reasonable doubt that spirometry ought to be abandoned at this point in time
Present a proof of concept of a novel approach to the analysis of spirometry
Timeline of Spirometry and OS
Timeline of Spirometry and OS
1846 Hutchison publishes paper on VC in first 2130 subjects
1947 Tiffineau proposes timed FVCs
Timeline of Spirometry and OS
1846 Hutchison publishes paper on VC in first 2130 subjects
1947 Tiffineau proposes timed FVCs
1951 duBois presents first abstract on OS
1956 duBois publishes first paper on OS
Timeline of Spirometry and OS
1846 Hutchison publishes paper on VC in first 2130 subjects
1947 Tiffineau proposes timed FVCs
1951 duBois presents first abstract on OS
1956 duBois publishes first paper on OS
1958 Hyatt describes F-V loop
1971 Menkes & Permitt introduce moment analysis
1978 Mead introduced slope ratio
1979 Mead proposes interrupted F-V loop
Timeline of Spirometry and OS
1846 Hutchison publishes paper on VC in first 2130 subjects
1947 Tiffineau proposes timed FVCs
1951 duBois presents first abstract on OS
1956 duBois publishes first paper on OS
1958 Hyatt describes F-V loop
1971 Menkes & Permitt introduce moment analysis
1978 Mead introduced slope ratio
1979 Mead proposes interrupted F-V loop
1992 First commercial OS system marketed
Timeline of Spirometry and OS
1846 Hutchison publishes paper on VC in first 2130 subjects
1947 Tiffineau proposes timed FVCs
1951 duBois presents first abstract on OS
1956 duBois publishes first paper on OS
1958 Hyatt describes F-V loop
1971 Menkes & Permitt introduce moment analysis
1978 Mead introduced slope ratio
1979 Mead proposes interrupted F-V loop
1992 First commercial OS system marketed
2016 Usmani - Dandurand debate
Then and Now
Hutchinson, Med Chir Trans 1846;29:137 Grimby et al., JCI 1968;47:1455
Spirometry vs. OS Advantages Spirometry OS
Cost € 1.4 K € 10-35 K
Availability Ubiquitous Rare
Portability Most 1/5
Longitudinal data 70 years 3 years
Treatment guidelines GINA/GOLD None
Intuitive concept Yes No
Disadvantages
inhomogeneities
Spirometry vs. OS Advantages Spirometry OS
Cost € 1.4 K € 10-35 K
Availability Ubiquitous Rare
Portability Most 1/5
Longitudinal data 70 years 3 years
Treatment guidelines GINA/GOLD None
Intuitive concept Yes No
Disadvantages
Forced manoeuvre Yes No
Insensitive
Small airways disease
Ventilatory inhomogeneities
Spirometry vs. OS Advantages Spirometry OS
Cost € 1.4 K € 10-35 K
Availability Ubiquitous Rare
Portability Most 1/5
Longitudinal data 70 years 3 years
Treatment guidelines GINA/GOLD None
Intuitive concept Yes No
Disadvantages
Forced manoeuvre Yes No
Insensitive
Small airways disease
Ventilatory inhomogeneities
Spirometry vs. OS Advantages Spirometry OS
Cost € 1.4 K € 10-35 K
Availability Ubiquitous Rare
Portability Most 1/5
Longitudinal data 70 years 3 years
Treatment guidelines GINA/GOLD None
Intuitive concept Yes No
Disadvantages
Forced manoeuvre Yes No
Insensitive
Small airways disease
Ventilatory inhomogeneities
Spirometry vs. OS Advantages Spirometry OS
Cost € 1.4 K € 10-35 K
Availability Ubiquitous Rare
Portability Most 1/5
Longitudinal data 70 years 3 years
Treatment guidelines GINA/GOLD None
Intuitive concept Yes No
Disadvantages
Forced manoeuvre Yes No
Insensitive
Small airways disease
Ventilatory inhomogeneities
Spirometry vs. OS Advantages Spirometry OS
Cost € 1.4 K € 10-35 K
Availability Ubiquitous Rare
Portability Most 1/5
Longitudinal data 70 years 3 years
Treatment guidelines GINA/GOLD None
Intuitive concept Yes No
Disadvantages
Forced manoeuvre Yes No
Insensitive
Small airways disease
Ventilatory inhomogeneities ?
Need for Better Biomarker Clear
Jones, Thorax 2001;56:880–887
Need for Better Biomarker Clear
Dandurand et al, ERS Congress 2013
Debate Not New
Chest 2015;148:1131-1139
But Is It Fare to Compare?
FEV1
vs.
OS
Thank You
But Is It Fare to Compare?
FEV1
Single parameter
Typically 15-30 data points
OS
6 parameters (R5, R5-20, X5, Fres, AX, ΔX5)
Typically 12,228 data points
Example Expiratory Spirogram
Index Base %Pred
FEV1 2.91 l 102%
FEV3 3.56 l
FVC 3.87 l 105%
PEF 498l/min 108%
FEV1/FVC 75% 100%
FEV3/FVC 91%
FEF75 5.87 l/s 86%
FEF50 2.66 l/s 67%
FEF25 0.91 l/s 68%
FEF25-75 2.23 l/s 73% 0
1
2
3
4
5
6
7
8
9
0 1 2 3 4
Flo
w (
L/s)
Volume (L)
0
1
2
3
4
0 1 2 3 4 5 6 7
Vo
lum
e (
L)
Time (s)
MP, 2015-12-04
Example Expiratory Spirogram
Index Base %Pred
FEV1 2.91 l 102%
FEV3 3.56 l
FVC 3.87 l 105%
PEF 498l/min 108%
FEV1/FVC 75% 100%
FEV3/FVC 91%
FEF75 5.87 l/s 86%
FEF50 2.66 l/s 67%
FEF25 0.91 l/s 68%
FEF25-75 2.23 l/s 73% 0
1
2
3
4
5
6
7
8
9
0 1 2 3 4
Flo
w (
L/s)
Volume (L)
37 data points
0
1
2
3
4
0 1 2 3 4 5 6 7
Vo
lum
e (
L)
Time (s)
MP, 2015-12-04
22 data points
Example OS Study
MP, 2015-12-04
Example OS Study
MP, 2015-12-04
256 Hz X 16 sec = 4096 data points 12,288 data points
But Is It Fare to Compare?
FEV1
Single parameter
Typically 15-30 data points
OS
6 parameters (R5, R5-20, X5, Fres, AX, ΔX5)
Typically 12,228 data points
But Is It Fare to Compare?
FEV1
Single parameter
Typically 15-30 data points
OS
6 parameters (R5, R5-20, X5, Fres, AX, ΔX5)
Typically 12,228 data points
No, but’s time to level the playing field!
But Is It Fare to Compare?
FEV1
Single parameter
Typically 15-30 data points
OS
6 parameters (R5, R5-20, X5, Fres, AX, ΔX5)
Typically 12,228 data points
No, but’s time to level the playing field!
…but first
What to We Wish to Achieve?
What to We Wish to Achieve? Detect obstructive lung disease at an earlier stage
What to We Wish to Achieve? Detect obstructive lung disease at an earlier stage
Dandurand et al, Chest 2015
What to We Wish to Achieve? Detect obstructive lung disease at an earlier stage
Dandurand et al, Chest 2015
What to We Wish to Achieve? Detect obstructive lung disease at an earlier stage
Dandurand et al, Chest 2015
What to We Wish to Achieve? Detect obstructive lung disease at an earlier stage
Dandurand et al, Chest 2015
What to We Wish to Achieve? Detect obstructive lung disease at an earlier stage
Detect therapeutic responses more reliably
What to We Wish to Achieve? Detect obstructive lung disease at an earlier stage
Detect therapeutic responses more reliably
Ideally, approximate small airways function test results
Multi-breath nitrogen washout
Frequency dependence of compliance
What to We Wish to Achieve? Detect obstructive lung disease at an earlier stage
Detect therapeutic responses more reliably
Ideally, approximate small airways function test results
Multi-breath nitrogen washout
Frequency dependence of compliance
Can this be done with spirometry?
What to We Wish to Achieve? Detect obstructive lung disease at an earlier stage
Detect therapeutic responses more reliably
Ideally, approximate small airways function test results
Multi-breath nitrogen washout
Frequency dependence of compliance
Can this be done with spirometry?
Certainly not as conventionally analyzed, but…
Spirometric Indices Volume and Flow
FVC
FEV0.5, 1, 2, 3, 6
MMEF
Spirometric Indices Volume and Flow
FVC
FEV0.5, 1, 2, 3, 6
MMEF
PEFR
V̇75, 50, 25, V̇75/V̇25, V̇50/V̇25
Spirometric Indices Volume and Flow
FVC
FEV0.5, 1, 2, 3, 6
MMEF
PEFR
V̇75, 50, 25, V̇75/V̇25, V̇50/V̇25
Time
Moments about origin
α1 , α2 , α3 , α4
Moments about mean
μ2 , μ3 , μ4
Spirometric Indices Volume and Flow
FVC
FEV0.5, 1, 2, 3, 6
MMEF
PEFR
V̇75, 50, 25, V̇75/V̇25, V̇50/V̇25
Time
Moments about origin
α1 , α2 , α3 , α4
Moments about mean
μ2 , μ3 , μ4
Nondementionalized Volume and Flow
FEV0.5, 1, 2, 3, 6 / FVC
MMEF / FVC
PEFR / FVC
V̇75, 50, 25 / FVC
Nondementionalized Time
Moments about origin
α1/t, α2/t , α3/t, α4/t
Moments about mean
μ2/t , μ3/t , μ4/t
Spirometric Indices Volume and Flow
FVC
FEV0.5, 1, 2, 3, 6
MMEF
PEFR
V̇75, 50, 25, V̇75/V̇25, V̇50/V̇25
Time
Moments about origin
α1 , α2 , α3 , α4
Moments about mean
μ2 , μ3 , μ4
Nondementionalized Volume and Flow
FEV0.5, 1, 2, 3, 6 / FVC
MMEF / FVC
PEFR / FVC
V̇75, 50, 25 / FVC
Nondementionalized Time
Moments about origin
α1/t, α2/t , α3/t, α4/t
Moments about mean
μ2/t , μ3/t , μ4/t
Spirometric Indices Volume and Flow
FVC
FEV0.5, 1, 2, 3, 6
MMEF
PEFR
V̇75, 50, 25, V̇75/V̇25, V̇50/V̇25
Time
Moments about origin
α1 , α2 , α3 , α4
Moments about mean
μ2 , μ3 , μ4
Nondementionalized Volume and Flow
FEV0.5, 1, 2, 3, 6 / FVC
MMEF / FVC
PEFR / FVC
V̇75, 50, 25 / FVC
Nondementionalized Time
Moments about origin
α1/t, α2/t , α3/t, α4/t
Moments about mean
μ2/t , μ3/t , μ4/t
Others: Slope ratio of Mead, ΔV̇, V̇iso
Example Expiratory Spirogram
Index Base %Pred
FEV1 2.91 l 102%
FEV3 3.56 l
FVC 3.87 l 105%
PEF 498l/min 108%
FEV1/FVC 75% 100%
FEV3/FVC 91%
FEF75 5.87 l/s 86%
FEF50 2.66 l/s 67%
FEF25 0.91 l/s 68%
FEF25-75 2.23 l/s 73% 0
1
2
3
4
5
6
7
8
9
0 1 2 3 4
Flo
w (
L/s)
Volume (L)
0
1
2
3
4
0 1 2 3 4 5 6 7
Vo
lum
e (
L)
Time (s)
MP, 2015-12-04
Comparing Spirogram Volumes
0
1
2
3
4
5
6
7
8
9
0 1 2 3 4
Flo
w (
L/s)
Volume (L)
0
1
2
3
4
0 1 2 3 4 5 6 7
Vo
lum
e (
L)
Time (s)
MP, 2015-12-04 JT, 2016-02-05
MP JT
Age 68 78
Sex M F
Ht (cm) 170 152
Wt (kg) 80 56
BMI 28 24
0.0
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 5 6
Vo
lum
e /
FV
C
Time (s)
Nondementionalized Spirograms
MP, 2015-12-04 JT, 2016-02-05
MP JT
Age 68 78
Sex M F
Ht (cm) 170 152
Wt (kg) 80 56
BMI 28 24
Comparing Spirogram Times
JC, 2015-11-20 CR, 2015-11-20
JC CR
Age 62 62
Sex F F
Ht (cm) 158 154
Wt (kg) 45 70
BMI 18 30
0
1
2
3
4
5
0 1 2 3 4
Flo
w (
L/s)
Volume (L)
0
1
2
3
4
0 2 4 6 8 10 12
Vo
lum
e (L
)
Time (s)
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Nondementionalized Spirograms
JC, 2015-11-20 CR, 2015-11-20
JC CR
Age 62 62
Sex F F
Ht (cm) 158 154
Wt (kg) 45 70
BMI 18 30
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
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0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
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0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
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0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
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1.0
0.0 0.2 0.4 0.6 0.8 1.0
Vo
lum
e /
FV
C
Time / Total Time
Time Domain Analysis - Moments
JC, 2015-11-20 CR, 2015-11-20
0.0
0.2
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α1 α21/2 α3
1/3 α41/4 μ2
1/2 μ31/3 μ4
1/4
CR 0.161 0.060 0.036 0.027 0.034 2.549 6.796
JC 0.243 0.130 0.090 0.070 0.072 1.310 0.633
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Novel Spirometric Analysis
Novel Spirometric Analysis 30 asthmatics undergoing simultaneous OS and spirometry
Novel Spirometric Analysis 30 asthmatics undergoing simultaneous OS and spirometry
Derive absolute and nondementionalized volume, flow and time domain indices
Novel Spirometric Analysis 30 asthmatics undergoing simultaneous OS and spirometry
Derive absolute and nondementionalized volume, flow and time domain indices
Perform pairwise analysis of 46 of these indices vs. OS parameters
Novel Spirometric Analysis 30 asthmatics undergoing simultaneous OS and spirometry
Derive absolute and nondementionalized volume, flow and time domain indices
Perform pairwise analysis of 46 of these indices vs. OS parameters
Chose a reasonable number of indices based on
Pearson’s r
Intuitive judgment
Novel Spirometric Analysis 30 asthmatics undergoing simultaneous OS and spirometry
Derive absolute and nondementionalized volume, flow and time domain indices
Perform pairwise analysis of 46 of these indices vs. OS parameters
Chose a reasonable number of indices based on
Pearson’s r
Intuitive judgment
Build a model using multiple linear regression
30 Asthma Clinic Subjects Age (mean years±SD) 66 ± 15 Sex (M:F) 13 : 17
BMI (m/kg2) 29 ± 4 ACQ 5 ± 5
FEV1 (L) 2.06 ± 0.74 FEV1 (% predicted) 87 ± 23 FVC (L) 3.06 ± 0.92 FVC (% predicted) 104 ± 22 FEV1/FVC (%) 66 ± 12 MMEF (L/s) 1.29 ± 0.79 MMEF (% predicted) 43 ± 21
R5 (cmH2O/L/s) 4.33 ± 1.73 R5-19 (cmH2O/L/s) 1.09 ± 1.08 X5 (cmH2O/L/s) -2.23 ± 2.01 Fres (Hz) 21.85 ± 9.63 AX (cmH2O/L/s • Hz) 21.20 ± 21.61
Pairwise Correlation for ln R5-19
Index r p Index r p Index r p FVC -0.25 0.18 α1 0.49 0.01 α1mode 0.50 0.01 FEV1 -0.46 0.01 α2
1/2 0.41 0.02 α2mode1/2 0.41 0.02
FEV1/FVC -0.53 0.00 α31/3 0.32 0.09 α3mode
1/3 0.32 0.09 FEV3 -0.41 0.02 α4
1/4 0.25 0.18 α4mode1/4 0.25 0.18
FEV3/FVC -0.55 0.00 μ21/2 0.39 0.03 μ2mode
1/2 0.35 0.05 PERF -0.26 0.17 μ3
1/3 -0.44 0.01 μ3mode1/3 -0.54 0.00
PERF/FVC -0.11 0.57 μ41/4 -0.47 0.01 μ4mode
1/4 -0.53 0.00 MMEF -0.63 0.00 α1/t 0.17 0.36 α1mode/t 0.27 0.14 MMEF/FVC -0.58 0.00 α2/t
1/2 0.33 0.08 α2mode/t1/2 0.34 0.06
V̇75 -0.50 0.01 α3/t1/3 0.27 0.14 α3mode/t
1/3 0.32 0.09
V̇75/FVC -0.38 0.04 α4/t1/4 0.16 0.39 α4mode/t
1/4 0.21 0.27
V̇50 -0.59 0.00 μ2/t1/2 0.45 0.01 μ2mode/t
1/2 0.42 0.02
V̇50/FVC -0.58 0.00 μ3/t1/3 -0.44 0.01 μ3mode/t
1/3 -0.54 0.00
V̇25 -0.63 0.00 μ4/t1/4 -0.47 0.01 μ4mode/t
1/4 -0.53 0.00
V̇25/FVC -0.59 0.00
V̇75/V̇25 0.27 0.15
V̇50/V̇25 0.20 0.30
Pairwise Correlation for ln R5-19
Index r p Index r p Index r p FVC -0.25 0.18 α1 0.49 0.01 α1mode 0.50 0.01 FEV1 -0.46 0.01 α2
1/2 0.41 0.02 α2mode1/2 0.41 0.02
FEV1/FVC -0.53 0.00 α31/3 0.32 0.09 α3mode
1/3 0.32 0.09 FEV3 -0.41 0.02 α4
1/4 0.25 0.18 α4mode1/4 0.25 0.18
FEV3/FVC -0.55 0.00 μ21/2 0.39 0.03 μ2mode
1/2 0.35 0.05 PERF -0.26 0.17 μ3
1/3 -0.44 0.01 μ3mode1/3 -0.54 0.00
PERF/FVC -0.11 0.57 μ41/4 -0.47 0.01 μ4mode
1/4 -0.53 0.00 MMEF -0.63 0.00 α1/t 0.17 0.36 α1mode/t 0.27 0.14 MMEF/FVC -0.58 0.00 α2/t
1/2 0.33 0.08 α2mode/t1/2 0.34 0.06
V̇75 -0.50 0.01 α3/t1/3 0.27 0.14 α3mode/t
1/3 0.32 0.09
V̇75/FVC -0.38 0.04 α4/t1/4 0.16 0.39 α4mode/t
1/4 0.21 0.27
V̇50 -0.59 0.00 μ2/t1/2 0.45 0.01 μ2mode/t
1/2 0.42 0.02
V̇50/FVC -0.58 0.00 μ3/t1/3 -0.44 0.01 μ3mode/t
1/3 -0.54 0.00
V̇25 -0.63 0.00 μ4/t1/4 -0.47 0.01 μ4mode/t
1/4 -0.53 0.00
V̇25/FVC -0.59 0.00
V̇75/V̇25 0.27 0.15
V̇50/V̇25 0.20 0.30
Pairwise Correlation for ln R5-19
Index r p Index r p Index r p FVC -0.25 0.18 α1 0.49 0.01 α1mode 0.50 0.01 FEV1 -0.46 0.01 α2
1/2 0.41 0.02 α2mode1/2 0.41 0.02
FEV1/FVC -0.53 0.00 α31/3 0.32 0.09 α3mode
1/3 0.32 0.09 FEV3 -0.41 0.02 α4
1/4 0.25 0.18 α4mode1/4 0.25 0.18
FEV3/FVC -0.55 0.00 μ21/2 0.39 0.03 μ2mode
1/2 0.35 0.05 PERF -0.26 0.17 μ3
1/3 -0.44 0.01 μ3mode1/3 -0.54 0.00
PERF/FVC -0.11 0.57 μ41/4 -0.47 0.01 μ4mode
1/4 -0.53 0.00 MMEF -0.63 0.00 α1/t 0.17 0.36 α1mode/t 0.27 0.14 MMEF/FVC -0.58 0.00 α2/t
1/2 0.33 0.08 α2mode/t1/2 0.34 0.06
V̇75 -0.50 0.01 α3/t1/3 0.27 0.14 α3mode/t
1/3 0.32 0.09
V̇75/FVC -0.38 0.04 α4/t1/4 0.16 0.39 α4mode/t
1/4 0.21 0.27
V̇50 -0.59 0.00 μ2/t1/2 0.45 0.01 μ2mode/t
1/2 0.42 0.02
V̇50/FVC -0.58 0.00 μ3/t1/3 -0.44 0.01 μ3mode/t
1/3 -0.54 0.00
V̇25 -0.63 0.00 μ4/t1/4 -0.47 0.01 μ4mode/t
1/4 -0.53 0.00
V̇25/FVC -0.59 0.00
V̇75/V̇25 0.27 0.15
V̇50/V̇25 0.20 0.30
Pairwise Correlation for ln R5-19
Index r p Index r p Index r p FVC -0.25 0.18 α1 0.49 0.01 α1mode 0.50 0.01 FEV1 -0.46 0.01 α2
1/2 0.41 0.02 α2mode1/2 0.41 0.02
FEV1/FVC -0.53 0.00 α31/3 0.32 0.09 α3mode
1/3 0.32 0.09 FEV3 -0.41 0.02 α4
1/4 0.25 0.18 α4mode1/4 0.25 0.18
FEV3/FVC -0.55 0.00 μ21/2 0.39 0.03 μ2mode
1/2 0.35 0.05 PERF -0.26 0.17 μ3
1/3 -0.44 0.01 μ3mode1/3 -0.54 0.00
PERF/FVC -0.11 0.57 μ41/4 -0.47 0.01 μ4mode
1/4 -0.53 0.00 MMEF -0.63 0.00 α1/t 0.17 0.36 α1mode/t 0.27 0.14 MMEF/FVC -0.58 0.00 α2/t
1/2 0.33 0.08 α2mode/t1/2 0.34 0.06
V̇75 -0.50 0.01 α3/t1/3 0.27 0.14 α3mode/t
1/3 0.32 0.09
V̇75/FVC -0.38 0.04 α4/t1/4 0.16 0.39 α4mode/t
1/4 0.21 0.27
V̇50 -0.59 0.00 μ2/t1/2 0.45 0.01 μ2mode/t
1/2 0.42 0.02
V̇50/FVC -0.58 0.00 μ3/t1/3 -0.44 0.01 μ3mode/t
1/3 -0.54 0.00
V̇25 -0.63 0.00 μ4/t1/4 -0.47 0.01 μ4mode/t
1/4 -0.53 0.00
V̇25/FVC -0.59 0.00
V̇75/V̇25 0.27 0.15
V̇50/V̇25 0.20 0.30
The R5-19 Model Using Spirometry
The R5-19 Model Using Spirometry
ln R5-19 =
The R5-19 Model Using Spirometry
ln R5-19 = - 2•FVC + 2•FEV1 + 44•MMEF/FVC
The R5-19 Model Using Spirometry
ln R5-19 = - 2•FVC + 2•FEV1 + 44•MMEF/FVC
- 2•V̇75/FVC - 22•V̇50/FVC - 4•V̇25/FVC
The R5-19 Model Using Spirometry
ln R5-19 = - 2•FVC + 2•FEV1 + 44•MMEF/FVC
- 2•V̇75/FVC - 22•V̇50/FVC - 4•V̇25/FVC
-286•α1mode/t + 956• α2mode/t1/2
-416• α3mode/t1/3 - 10•α4mode/t
1/4 + 34
The R5-19 Model Using Spirometry
ln R5-19 = - 2•FVC + 2•FEV1 + 44•MMEF/FVC
- 2•V̇75/FVC - 22•V̇50/FVC - 4•V̇25/FVC
-286•α1mode/t + 956• α2mode/t1/2
-416• α3mode/t1/3 - 10•α4mode/t
1/4 + 34
r = 0.86
Conclusions
Conclusions Spirometry is cheap, widely available, well understood and
has almost 70 years of longitudinal validation
Conclusions Spirometry is cheap, widely available, well understood and
has almost 70 years of longitudinal validation
Multiple regression of selected spirometric indices seems to approximate frequency dependence of resistance and hence, small airway disease
Conclusions Spirometry is cheap, widely available, well understood and
has almost 70 years of longitudinal validation
Multiple regression of selected spirometric indices seems to approximate frequency dependence of resistance and hence, small airway disease
If so, it is premature to recommend abandoning spirometry in favour of OS
Conclusions Spirometry is cheap, widely available, well understood and
has almost 70 years of longitudinal validation
Multiple regression of selected spirometric indices seems to approximate frequency dependence of resistance and hence, small airway disease
If so, it is premature to recommend abandoning spirometry in favour of OS
Further work is necessary to validate and improve upon this novel approach to the spirometric analysis of lung mechanics
To FEV1 or Not…Rebuttal
“The proof [of concept]
is in the pudding”
Proof of Concept: R5-19 Modeling Derivation Cohort Validation Cohort
n=30 n=14 Age (mean years ± SE) 66 ± 3 68 ± 3 Sex (M:F) 13 : 17 5 : 9 BMI (Kg/m2) 29 ± 1 28 ± 1 ACQ 5 ± 1 2 ± 1
FEV1 (L) 2.06 ± 0.13 2.02 ± 0.14 FEV1 (% predicted) 87 ± 4 87 ± 4 FVC (L) 3.06 ± 0.17 2.93 ± 0 FVC (% predicted) 104 ± 4 102 ± 4.16 FEV1/FVC (%) 66 ± 2 70 ± 3 MMEF (L/s) 1.29 ± 0.14 1.27 ± 0.12 MMEF (% predicted) 43 ± 4 45 ± 3
R5 (cmH2O/L/s) 4.33 ± 0.32 4.03 ± 0.29 R5-19 (cmH2O/L/s) 1.09 ± 0.20 0.79 ± 0.21 X5 (cmH2O/L/s) -2.23 ± 0.37 -1.67 ± 0.28 Fres (Hz) 21.85 ± 1.76 22.70 ± 1.85 AX (cmH2O/L/s • Hz) 21.20 ± 3.95 17.18 ± 3.47
Proof of Concept: R5-19 Modeling Derivation Cohort Validation Cohort
n=30 n=14 Age (mean years ± SE) 66 ± 3 68 ± 3 Sex (M:F) 13 : 17 5 : 9 BMI (Kg/m2) 29 ± 1 28 ± 1 ACQ 5 ± 1 2 ± 1
FEV1 (L) 2.06 ± 0.13 2.02 ± 0.14 FEV1 (% predicted) 87 ± 4 87 ± 4 FVC (L) 3.06 ± 0.17 2.93 ± 0 FVC (% predicted) 104 ± 4 102 ± 4.16 FEV1/FVC (%) 66 ± 2 70 ± 3 MMEF (L/s) 1.29 ± 0.14 1.27 ± 0.12 MMEF (% predicted) 43 ± 4 45 ± 3
R5 (cmH2O/L/s) 4.33 ± 0.32 4.03 ± 0.29 R5-19 (cmH2O/L/s) 1.09 ± 0.20 0.79 ± 0.21 X5 (cmH2O/L/s) -2.23 ± 0.37 -1.67 ± 0.28 Fres (Hz) 21.85 ± 1.76 22.70 ± 1.85 AX (cmH2O/L/s • Hz) 21.20 ± 3.95 17.18 ± 3.47
Proof of Concept: R5-19 Modeling Derivation Cohort Validation Cohort
n=30 n=14 Age (mean years ± SE) 66 ± 3 68 ± 3 Sex (M:F) 13 : 17 5 : 9 BMI (Kg/m2) 29 ± 1 28 ± 1 ACQ 5 ± 1 2 ± 1
FEV1 (L) 2.06 ± 0.13 2.02 ± 0.14 FEV1 (% predicted) 87 ± 4 87 ± 4 FVC (L) 3.06 ± 0.17 2.93 ± 0 FVC (% predicted) 104 ± 4 102 ± 4.16 FEV1/FVC (%) 66 ± 2 70 ± 3 MMEF (L/s) 1.29 ± 0.14 1.27 ± 0.12 MMEF (% predicted) 43 ± 4 45 ± 3
R5 (cmH2O/L/s) 4.33 ± 0.32 4.03 ± 0.29 R5-19 (cmH2O/L/s) 1.09 ± 0.20 0.79 ± 0.21 X5 (cmH2O/L/s) -2.23 ± 0.37 -1.67 ± 0.28 Fres (Hz) 21.85 ± 1.76 22.70 ± 1.85 AX (cmH2O/L/s • Hz) 21.20 ± 3.95 17.18 ± 3.47
Proof of Concept: R5-19 Modeling Derivation Cohort Validation Cohort
n=30 n=14 Age (mean years ± SE) 66 ± 3 68 ± 3 Sex (M:F) 13 : 17 5 : 9 BMI (Kg/m2) 29 ± 1 28 ± 1 ACQ 5 ± 1 2 ± 1
FEV1 (L) 2.06 ± 0.13 2.02 ± 0.14 FEV1 (% predicted) 87 ± 4 87 ± 4 FVC (L) 3.06 ± 0.17 2.93 ± 0 FVC (% predicted) 104 ± 4 102 ± 4.16 FEV1/FVC (%) 66 ± 2 70 ± 3 MMEF (L/s) 1.29 ± 0.14 1.27 ± 0.12 MMEF (% predicted) 43 ± 4 45 ± 3
R5 (cmH2O/L/s) 4.33 ± 0.32 4.03 ± 0.29 R5-19 (cmH2O/L/s) 1.09 ± 0.20 0.79 ± 0.21 X5 (cmH2O/L/s) -2.23 ± 0.37 -1.67 ± 0.28 Fres (Hz) 21.85 ± 1.76 22.70 ± 1.85 AX (cmH2O/L/s • Hz) 21.20 ± 3.95 17.18 ± 3.47
Proof of Concept: R5-19 Modeling Derivation Cohort Validation Cohort
n=30 n=14 Age (mean years ± SE) 66 ± 3 68 ± 3 Sex (M:F) 13 : 17 5 : 9 BMI (Kg/m2) 29 ± 1 28 ± 1 ACQ 5 ± 1 2 ± 1
FEV1 (L) 2.06 ± 0.13 2.02 ± 0.14 FEV1 (% predicted) 87 ± 4 87 ± 4 FVC (L) 3.06 ± 0.17 2.93 ± 0 FVC (% predicted) 104 ± 4 102 ± 4.16 FEV1/FVC (%) 66 ± 2 70 ± 3 MMEF (L/s) 1.29 ± 0.14 1.27 ± 0.12 MMEF (% predicted) 43 ± 4 45 ± 3
R5 (cmH2O/L/s) 4.33 ± 0.32 4.03 ± 0.29 R5-19 (cmH2O/L/s) 1.09 ± 0.20 0.79 ± 0.21 X5 (cmH2O/L/s) -2.23 ± 0.37 -1.67 ± 0.28 Fres (Hz) 21.85 ± 1.76 22.70 ± 1.85 AX (cmH2O/L/s • Hz) 21.20 ± 3.95 17.18 ± 3.47
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Proof of Concept: R5-19 Modeling
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Proof of Concept: R5-19 Modeling
Proof of Concept: R5-19 Modeling
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Proof of Concept: R5-19 Modeling
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Proof of Concept: R5-19 Modeling
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Proof of Concept: R5-19 Modeling
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Proof of Concept: R5-19 Modeling
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Proof of Concept: R5-19 Modeling
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-19
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Proof of Concept: R5-19 Modeling
r=0.83
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-19
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Proof of Concept: R5-19 Modeling
r=0.83
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OS R5-19 (cmH2O/L/s)
Correct: 13/14 93%
Summary Spirometry may be comparable to OS for the detection
of small airway disease
There is reasonable doubt that spirometry ought to be abandoned at this point in time
Further work is warranted on novel approaches to the analysis of spirometry
“Don’t throw spirometry out with the bath water!”