Lung Function in the Era of the

Global Lung Initiative: Changing

how we think about lung function

Larry C. Lands, MD, PhDProfessor of Pediatrics, McGill University

Director, Pediatric Respiratory Medicine, MCH-MUHC

larry.lands@mcgill.ca

“Making a clinical diagnosis is an art, where test

results help to confirm or reject the diagnosis.”

Quanjer et al, ERJ 2012

What is Normal?

Sodium 140 mmol/L

Hemoglobin 180 g/L

FEV1 77% predicted

FEV1 across Ages

Stanojevic et al, AJRCCM 2009

Males Females

Cross-Age Predictions

FVC

FEV1

FEF25-75

Stanojevic et al, ERJ 2010

The Bell Curve

Statistical Modeling for the GLI

Lower (Upper) Limit of Normal: LLN (ULN)

Comprises 5% of the population

Modeling based on height2.5

Takes into account variability between individuals

Uses z-scores (based on SD)

Variations Between Individuals

Coefficient of Variation = Standard Deviation/Mean

The SD normalized for its mean value

By tradition, we have assumed a 10% coefficient of

variation, so

2 X CV is ±20%, ie 80-120% considered as

NORMAL

WHAT IF THE CV WAS MORE THAN 10%?

Coefficient of Variation

FVC

FEV1

FEF25-75

Stanojevic et al, ERJ 2010

Z-scores To the Rescue

Z-score combines % predicted and the variation

between individuals “to give a single number that

accounts for age- and height-related lung function

variability expected within comparable healthy

individuals”

LLN of a z-score is -1.64 (lowest 5%)

ULN of a z-score is +1.64 (highest 5%)

Stanojevic et al, ERJ 2010

Going Global

Caucasians African-Americans

North East Asians South East Asians

Quanjer et al, ERJ 2012

Who’s Who?

White: Caucasian

Black: African-American

North-East Asian: North China, Korea

South-East Asia: South China, Thailand, Taiwan

Other: other groups or mixed ethnicity

Going Global-FEV1

Quanjer et al, ERJ 2012

Males Females

Going Global-Accuracy of Input Values

Quanjer et al, ERJ 2012

Entering 160 cm instead of 161 cm for height changes

the predicted value for FEV1 by 1.3%

Age needs to be to 1 decimal point: Using 14 years

instead 14.9 underestimates FEV1 by 4.7%

For a 14 year old male, combining these 2 errors would

result in a 6% difference in predicted value

Going Global-Coefficient of Variation

Quanjer et al, ERJ 2012

Males

Coefficient of Variation

FVC

FEV1

FEF25-75

Stanojevic et al, ERJ 2010

Going Global-5% LLN

Quanjer et al, ERJ 2012

Females

FEV1/FVC without GLI

Swanney et al, Thorax 2008; Hansen et al, Chest 2007

Problems with Fixed FEV1/FVC

Quanjer et al, ERJ 2012

FEV1/FVC with GLI

Quanjer et al, ERJ 2012

Males Females

Assessing Obstruction-Do we need FEF25-75?

Quanjer et al, ERJ 2014

% FVC, FEV1, FEV1/FVC

WNL and low FEF25-75

Assessing Obstruction-Do we need FEF25-75?

Lukic and Coates, Ped Pulmonol 2015

Going Global-Comparison with

Other Prediction Equations

Quanjer et al, ERJ 2012

Going Global-Test Interpretation

Quanjer et al, ERJ 2012

Using multiple tests that are physiologically linked and

applying the 5% LLN to each of them has a multiplicative

effect leading to more false positives

Combining FEV1, FVC, FEV1/FVC would give about

10% (10.4-10.6%) abnormal

Using the 2.5% (z-score: -1.96) reduces this to 5.6-

5.8% abnormal

Suggested:

For screening and case finding use -1.96 (2.5%)

For those with prior lung disease, borderline values

more likely to be associated with disease and so use -1.64

(5%)

Going Global-Test Interpretation

Culver et al, AJRCCM, 2017

Example 1

Mild Asthma with BD Response

Example 2

Moderate-severe Cystic Fibrosis

Example 3

Tracheal Rings

Lum S et al. Thorax 2012;67:A18

Copyright © BMJ Publishing Group Ltd & British Thoracic Society. All rights reserved.

UK Validation Study

Changes in Cormic Index (Sitting

Height/Standing Height)

Quanjer et al, Chest 201517 year old women in

Japan

FEV1

FVC

FEV1/FVC

Lum, PLOS ONE, 2016

South Asian Children

UK South Asian Children

FEV1

FVC

FEV1/FVC

Lum, PLOS ONE, 2016

South Asian Children (India)

South Asian Children

Centre B: Northern India

Arigliani, AJRCCM, 2017

African-American or

African

Oh, Canada!

Coates, Ann Am Thorac Soc, 2016

Hüls, PLOS ONE, 2016

Germany, Ja!

GLI May Not Always Apply

Abdullah et al, Respirology 2018

2003 2010 Δ/year

mean p mean p mean p

Fev1 (ml) Observed 1107.4 2435.9 180.4

Predicted 1123.2 2497.5 188.3

δ -15.8 NS -61.6 * -7.9 *

FVC (ml) Observed 1120.7 2824.1 233.4

Predicted 1216.0 2876.4 227.8

δ -95.2 ** -52.3 ** 5.6 **

FEV1/FVC (%) Observed 96.6 85.5 -1.57

Predicted 92.9 87.1 -0.8

δ 3.7 ** -2.4 ** -0.77 **

FEF25-75 (ml/s) Observed 1621.3 2766.9 152.8

Predicted 1602.6 2955.8 185.2

δ 18.7 NS -269.6 ** -32.3 **

Piccioni, BMC Pulm Med, 2015

Longitudinal Assessment

Piccioni, BMC Pulm Med, 2015

Longitudinal

Assessment

Armspan to Predict Height

Quanjer et al, ERJ 2014

Diffusing Capacity

Cooper et al, Breathe 2017

GLI DLCO for Caucasians

Compared to values frequently

used in devicesStanojevic et al, ERJ 2017

Ethnicity and Lung Volumes

Kirkby et al, Ped Pulmonol 2013

Conclusions

• Pulmonary function tests are clinical data with an

expected range of normal

• Generalized equations allows for measurement

across the age span and wider applicability

• More data on other population groups is required

• Using a 5% Lower Limit of Normal (LLN) allows for

more accurate classification of patients