Ron Dandurand presents novel spirometry analysis at Respiratory Effectiveness Group Summit

1. Ron Dandurand, MD Respiratory Effectiveness Group Summit Lyon, France April 15, 2016

2. Objectives

3. Objectives  Prove non-inferiority of spirometry

4. Objectives  Prove non-inferiority of spirometry  Raise reasonable doubt that spirometry ought to be abandoned at this point in time

5. Objectives  Prove non-inferiority of spirometry  Raise reasonable doubt that spirometry ought to be abandoned at this point in time

6. 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

7. Timeline of Spirometry and OS

8. Timeline of Spirometry and OS 1846 Hutchison publishes paper on VC in first 2130 subjects 1947 Tiffineau proposes timed FVCs

9. 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

10. 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

11. 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

12. 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

13. Then and Now Hutchinson, Med Chir Trans 1846;29:137 Grimby et al., JCI 1968;47:1455

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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 ?

20. Need for Better Biomarker Clear Jones, Thorax 2001;56:880–887

21. Need for Better Biomarker Clear Dandurand et al, ERS Congress 2013

22. Debate Not New Chest 2015;148:1131-1139

23. But Is It Fare to Compare? FEV1 vs. OS

24. Thank You

25. 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

26. 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 Flow(L/s) Volume (L) 0 1 2 3 4 0 1 2 3 4 5 6 7 Volume(L) Time (s) MP, 2015-12-04

27. 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 Flow(L/s) Volume (L) 37 data points 0 1 2 3 4 0 1 2 3 4 5 6 7 Volume(L) Time (s) MP, 2015-12-04 22 data points

28. Example OS Study MP, 2015-12-04

29. Example OS Study MP, 2015-12-04 256 Hz X 16 sec = 4096 data points 12,288 data points

30. 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

31. 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!

32. 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

33. What to We Wish to Achieve?

34. What to We Wish to Achieve?  Detect obstructive lung disease at an earlier stage

35. What to We Wish to Achieve?  Detect obstructive lung disease at an earlier stage Dandurand et al, Chest 2015

39. What to We Wish to Achieve?  Detect obstructive lung disease at an earlier stage  Detect therapeutic responses more reliably

40. 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

41. 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?

42. 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…

43. Spirometric Indices Volume and Flow  FVC  FEV0.5, 1, 2, 3, 6  MMEF

44. Spirometric Indices Volume and Flow  FVC  FEV0.5, 1, 2, 3, 6  MMEF  PEFR  V̇75, 50, 25, V̇75/V̇25, V̇50/V̇25

45. 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

46. 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

47. 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

48. 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

49. 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 Flow(L/s) Volume (L) 0 1 2 3 4 0 1 2 3 4 5 6 7 Volume(L) Time (s) MP, 2015-12-04

50. Comparing Spirogram Volumes 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 Flow(L/s) Volume (L) 0 1 2 3 4 0 1 2 3 4 5 6 7 Volume(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

51. 0.0 0.2 0.4 0.6 0.8 1.0 0 1 2 3 4 5 6 Volume/FVC 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

52. 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 Flow(L/s) Volume (L) 0 1 2 3 4 0 2 4 6 8 10 12 Volume(L) Time (s)

53. 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 Volume/FVC 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

54. 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 Volume/FVC Time / Total Time Time Domain Analysis - Moments JC, 2015-11-20 CR, 2015-11-20

98. α1 α2 1/2 α3 1/3 α4 1/4 μ2 1/2 μ3 1/3 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 Volume/FVC Time / Total Time Time Domain Analysis - Moments JC, 2015-11-20 CR, 2015-11-20

99. Novel Spirometric Analysis

100. Novel Spirometric Analysis  30 asthmatics undergoing simultaneous OS and spirometry

101. Novel Spirometric Analysis  30 asthmatics undergoing simultaneous OS and spirometry  Derive absolute and nondementionalized volume, flow and time domain indices

102. 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

103. 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

104. 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

105. 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

106. 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 α2mode 1/2 0.41 0.02 FEV1/FVC -0.53 0.00 α3 1/3 0.32 0.09 α3mode 1/3 0.32 0.09 FEV3 -0.41 0.02 α4 1/4 0.25 0.18 α4mode 1/4 0.25 0.18 FEV3/FVC -0.55 0.00 μ2 1/2 0.39 0.03 μ2mode 1/2 0.35 0.05 PERF -0.26 0.17 μ3 1/3 -0.44 0.01 μ3mode 1/3 -0.54 0.00 PERF/FVC -0.11 0.57 μ4 1/4 -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/t 1/2 0.34 0.06 V̇75 -0.50 0.01 α3/t 1/3 0.27 0.14 α3mode/t 1/3 0.32 0.09 V̇75/FVC -0.38 0.04 α4/t 1/4 0.16 0.39 α4mode/t 1/4 0.21 0.27 V̇50 -0.59 0.00 μ2/t 1/2 0.45 0.01 μ2mode/t 1/2 0.42 0.02 V̇50/FVC -0.58 0.00 μ3/t 1/3 -0.44 0.01 μ3mode/t 1/3 -0.54 0.00 V̇25 -0.63 0.00 μ4/t 1/4 -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

110. The R5-19 Model Using Spirometry

111. The R5-19 Model Using Spirometry ln R5-19 =

112. The R5-19 Model Using Spirometry ln R5-19 = - 2•FVC + 2•FEV1 + 44•MMEF/FVC

113. 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

114. 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/t 1/2 -416• α3mode/t 1/3 - 10•α4mode/t 1/4 + 34

115. 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/t 1/2 -416• α3mode/t 1/3 - 10•α4mode/t 1/4 + 34 r = 0.86

116. Conclusions

117. Conclusions  Spirometry is cheap, widely available, well understood and has almost 70 years of longitudinal validation

118. 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

119. 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

120. 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

122. To FEV1 or Not…Rebuttal “The proof [of concept] is in the pudding”

123. 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

128. 0.0 1.0 2.0 3.0 0.0 1.0 2.0 3.0 ModelledR5-19(cmH2O/L/s) OS R5-19 (cmH2O/L/s) Proof of Concept: R5-19 Modeling

129. 0.0 1.0 2.0 3.0 0.0 1.0 2.0 3.0 ModelledR5-19(cmH2O/L/s) OS R5-19 (cmH2O/L/s) Proof of Concept: R5-19 Modeling

130. Proof of Concept: R5-19 Modeling 0.0 1.0 2.0 3.0 0.0 1.0 2.0 3.0 ModelledR5-19(cmH2O/L/s) OS R5-19 (cmH2O/L/s)

145. 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 ModelledR5-19(cmH2O/L/s) OS R5-19 (cmH2O/L/s)

146. 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 ModelledR5-19(cmH2O/L/s) OS R5-19 (cmH2O/L/s) Correct: 13/14 93%

147. 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

148. “Don’t throw spirometry out with the bath water!”

Ron Dandurand presents novel spirometry analysis at Respiratory Effectiveness Group Summit

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Ron Dandurand presents novel spirometry analysis at Respiratory Effectiveness Group Summit