PRO/CON DEBATE: PRO To FEV1 or Not

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

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

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

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

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

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19 (

cmH

2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

r=0.83

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

OS R5-19 (cmH2O/L/s)

Proof of Concept: R5-19 Modeling

r=0.83

0.0

1.0

2.0

3.0

0.0 1.0 2.0 3.0

Mo

de

lled

R5

-19

(cm

H2O

/L/s

)

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!”