Normal Spirometric Reference Equations – When the Best Fit May Not be the Best Solution

Allan Coates, B Eng (Elect) MDCMUniversity of TorontoHospital for Sick Children, Toronto 2011 Canadian Respiratory

Conference

The “Holy Grail” of Reference Equations

Representative of the population of interest

One equation for all ages for each sexSimple to program into the spirometersSufficient numbers to give confidence to

the lower limit of normal (LLN)

Definitions of “Normal” ValuesAmerican Association of Clinical Chemistry

Based on “healthy” individualsPlus/minus 2 standard deviations or 95% of the

populationsClearly the variability of a value in the general

population whether or not associated with a “disease” will impact the range of values within 2 SD

How does this fit with our spirometry reference values?

Health vs Disease

If 1000 perfectly healthy individuals had spirometry preformed, 2.5% would be below 2 SD and 2.5% above

By definition, none would have diseaseHence any clinical decision based on

spirometric values would depend on pre test probability

Pre Test ProbabilityDefinition

Pretest Probability is defined as the probability of the target disorder before a diagnostic test result is known

In respiratory medicine, only extreme deviations from the reference values are pathognomonic for disease

Hence pretest probability is an essential part of diagnosis

Who is Healthy?NHANES III rejection criteria

Smoking (cigarettes, cigars, pipe)MD dx of asthma, chronic bronchitis, emphysemaWhistling or wheezing in chest (last 12 months and apart from

colds)Persistent cough for phlegmModerate shortness of breath

Of the 15,000 plus acceptable spirometry tracings where did this leave us?

Hankinson et al Am J Resp Crit Care Med 1999

15,503 Acceptable Adult TestsSmokers 7115 RemainingMD Dx asthma, COPD 6465 Remaining

Whistling or wheezing in chest 5934

RemainingPersistent cough and/or phlegm 5651

RemainingModerate shortness of breath 4803 RemainingOver 80 (too few observations) 4634

Remaining

In adults, the rejection rate was > 2/3Hankinson et al Am J Resp Crit Care Med 1999

What about Children?

There were 3917 good test in 8-16 year oldsRejection criteria

Smoking 3580 Remaining

Asthma, chronic bronchitis 3170 Remaining

Wheezing, cough, phlegm 2796 Remaining

In pediatric sample, the rejection rate was > 1/4

1 2 3 4 5 6 FEV1 in Liters

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This is a plot of the FEV1 measured from a group of normal, non-smoking men who were all 60 years old and 180 cm tall.

Ref: MR Miller – www.millermr.com

Lower Limit of Normal - Definition

The predicted value for FEV1 for someone in this group is 3.5L.

Predicted Value

The shaded area represents 5% of normal men, age 60, height 180 cm, with the lowest FEV1.

This defines the Lower Limit of Normal (LLN).

LLN for FEV1 for this group is 2.6L

5% of the population with normal lungs have FEV1 below LLN

95% of the population with normal lungs have FEV1 above LLN

1 2 3 4 5 6 FEV1 in Liters

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Lower Limit of Normal

5% 95 %

FEV1 values less than LLN are considered to be below normal

Controversies over LLNMost of us were trained on percent predicted and the

concept that FEV1 and FVC ≥ 80% was normalIn other words, we had our own concept of LLNIn fact, for NHANES III, for FVC, LLN is 84% predicted

for a tall young male and 75% for a short elderly femaleAll of us use ± 2 SD for electrolytes with normal (95% of

healthy) being inside 2 SDWe have better PFT data – Why not use it?

LLN for the FEV1/FVC ratio

NHANES III Hankinson, 1999While the ratio clearly decreases with age,these data showed that the variance was not affected by age or height. ie, homoscedastic.

Thanks to Bruce Culver

Concept of HomoscedasticityFor any given value of x (eg height)

the standard deviation of y (eg FEV1) is the same

The standard deviation depends on both variability and n

Reference values from small samples may not meet this requirement

NHANES III ApproachUsing a polynomial analysis for height and age,

attempted to have one equation for FEV1 and FVC

Had to settle for separate equations that joined at 18 for females and 20 for males

Also included values for FEV1/FVC, PEF, FEV6 and FEF25-75 and LLN for all parameters

Reference values for Caucasian, Mexican Americans and African Americans between 8 and 80 years

Problems with NHANES IIINumbers small at either extremes of the ages giving rise to

inhomoscedasticityExtrapolation to ages less than 8 gave rise to significant

over estimation in malesWhile the curves met at the 18 (♀s) and 20 years (♂s), the

curves were discontinuousDESPITE THESE CONCERNS, IT WAS WIDELY ACCEPTED

AND EASILY PROGRAMMED INTO SPIROMETRIC SOFTWARE

SolutionsThe values from pediatric series down to age

5 (Corey et al, Lebeques et al and Rosenthal et al were found to over lap where ages overlapped with NHANES and added to the series

New data analysis by the LMS methodResulting curves were “continuous”

.The distribution of the normal population at each point along the continuum is described by: mu the median sigma the coefficient of variance lambda an index of skewness.

The result is a series of equations linked by “splines” with coefficients from a set of look up tables, read by computer.

The method creates a smooth continuous predicted value (given by the median, mu )

LMS: lambda, mu, sigma Method

Stanojevic et al Am J Resp Care Med 2008

FM

LLN

Stanojevic2008

The sigma and lambda terms allow for the 5th

percentile LLN to be independently determined throughout the age-height spectrum FEV1/FVC ratio

Stanojevic compared to NHANES III

Stanojevic vs NHANESMores sophisticated statistical approach (Coles et

al 2008) with somewhat better “accuracy” overallSolved the problem of age limitation of NHANESSmoothed the 18 and 20 year transition pointsNHANES uses simple polynomial equation, easy

to program into a computer or hand calculatorThe complex mathematical approach of

Stanojevic has not been adapted (to date) in any commercial spirometric software

Reference Sources - Spirometry

NHANES III v Knudson, Crapo, Glindmeyer

Does One Set Over Another Really Make a Difference?

The difference between NNANES, Stanojevic and older series in adults is too small to result is serious clinical errors

This is not the case in children

Differences Depending on Equations

Hankinson breaks down when out of rangeKnudson equations just do not apply to young

Subbarao et al Pediatr Pulmonol 2004

ERS Task Force – Global Lungs InitiativeProject to collate available international lung function data to develop new reference equations.

Unlike the 1983-93 ECSC compilation which merged equations, the current effort has collected raw dataand is using the LMS method to analyze it.

Data from 150,000 individuals from 71 countries.

Co-chairs: Janet Stocks – UK, Xvar Baur – GermanyGraham Hall – ANZRS, Bruce Culver – ATS

Steering Comm includes: Phil Quanjer, Sonja Stanojevik,John Hankinson, Paul Enright.

ERS GlobalLungs Initiative

Problems and ChallengesNHANES III is from one data set gathered on the

same equipment under the same conditionsThe Stanojevic data is a composite of 4 sets from

different countries and different equipmentThe ERS Task Force will have the same problems

with multi site challengesThe challenge is enough numbers to have

confidence in the LLN but have identical methodology and homogeneous sample

What to Do?NHANES III is the largest data set to date and while

the polynomial approach may not be as scientific as the LMU approach, few if any clinical errors would occur for patients ≥ 8 years

The Stanojevic analysis is the best available and while cumbersome, can be used for ≥ 5 years

New Canadian data is being analyzed and should be available in the next 18 months

Conclusions

We do not have a perfect data set yet so reference equations are less than absolute ESPECIALLY FOR NON CAUCASIANS

We have much more confidence and better data on the LLN

There will always be a certain inaccuracy in the application of the results of any pulmonary function test, especially near the LLN