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Background

The Global Initiative for Obstructive Lung Disease, GOLD, has set out to raise clinical interest in the diagnosis and management of chronic obstructive pulmonary disease across the world [ 1 ] with the aim "to improve prevention and treatment of this lung disease". The GOLD organisation is a committee of leaders in the field which is sponsored by 14 pharmaceutical companies with an interest in this area of medical practice. It was set up in 1997 with the collaboration of the National Heart, Lung, and Blood Institute, National Institutes of Health, USA, and the World Health Organization.

GOLD has arbitrarily defined COPD on clinical and physiological criteria that have been argued to be not based on scientific evidence [ 2 ]. The GOLD definition is that COPD should be considered in any patient with symptoms of cough, sputum production, or dyspnoea, and/or a history of exposure to risk factors for the disease. The diagnosis is confirmed by spirometry. GOLD state that a post bronchodilator FEV1 < 80% of the predicted value and an FEV1×100/FVC (FEV1%) of < 70% confirms the presence of airflow limitation that is not fully reversible.

The GOLD approach has been followed in the UK by the National Institute for Health and Clinical Excellence (NICE) setting out guidelines for the management of COPD [ 3 ] indicating that any patient over the age of 35 with a risk factor for COPD and presenting with exertional breathlessness, chronic cough, regular sputum production, frequent winter bronchitis or wheeze should have the diagnosis confirmed by spirometry.

Thus healthcare services are now being encouraged to make the diagnosis of this disease in the community.

There are two reasons to question the GOLD definition of airflow limitation. Firstly the use of percent of predicted values for FEV1 as a method for defining levels of abnormality of lung function is supported neither by the American Thoracic Society (ATS) nor by the European Respiratory Society (ERS) [ 4 ].

Secondly the use of a single cut off for FEV1% of 70% to define the limit of normality for this index is also not supported by the ATS or ERS.

The fact that the arbitrary definition may lead to an age bias in the diagnosis of COPD has already been presented [ 5-10 ] and we will now explore the reason behind this in more detail.

Defining Abnormality in Lung Function Data

When an individual records their spirometry for the first time the clinician will want to know if the result is acceptable. The clinician needs to know if the result is within the expected range for someone of their age, sex, height and ethnicity (all factors known to influence their lung function results).

The best method to determine whether the result is normal is to calculate how far the subject's result is from their predicted value and express this in terms of the number of standard deviations from predicted the value is. This result is called the "Standardised Residual" (SR) and is given by: SR = ( Recorded - Predicted )/RSD

Plot of FEV1 data showing definition of a residual
RSD is the residual standard deviation from the prediction equation used. The term residual refers to the deviation a given subject's result is from the predicted value. In the Figure opposite the data value at 2.1 L has a residual from the predicted line for this subject's age and height of 1.8 L. This residual is then standardised by the spread (standard deviation) of these residuals found in the population used for the prediction.

Calculating the predicted value is usually done using a prediction equation taken from a population of comparable subjects and using equipment similar to that used for the subject's recording. For example the ECCS equation for FEV1 in men [ 11 ] is:

Predicted FEV1 = 4 .301 x height in metres - age x 0.029 - 2.492

The residual standard deviation for this regression equation is 0.51 Litres. So for a subject aged 45 yrs of height 1.87 metres who records an FEV1 of 3.653 Litres his predicted is given by:

Predicted FEV1 = 4.301 x 1.87 - 45 x 0 .029 -  2.492

That is   8.043  -  1.305  - 2.492   =  4.246 litres


This man's recording is  (3.653 - 4.246) / 0.51 standardised residuals from predicted, which equals - 1.186 SR from predicted. If we accept 1.645 SR below predicted as defining the LLN this result is within the normal range.

Setting the LLN at 1.645 below predictedWhy is the LLN set at 1.645 SR below predicted?

The Figure to the right shows a plot of the FEV1 values from a sample population of normal men of the same age and height with the average value found being 3.5 L and the standard deviation of the spread of results is 0.5 L. For a subject with FEV1 of 2.678 L this is 1.645 SD below the predicted mean, that is 3.5 L minus (1.645 x 0.5), and means that 5% of the normal population have FEV1 values lower than this. The grey shaded area in the graph is 5% of the total area under the graph.

If we define the Lower Limit of Normal (LLN) as 1.645 SD below the predicted in effect we are accepting a false positive rate of 5% in identifying subjects as abnormal. If we chose the LLN as 1.96 SD below predicted we would accept a false positive rate of 2.5%. The ATS and ERS endorse using the LLN as 1.645 SD below predicted [ 4 ].

How does GOLD define the presence of airflow limitation?

Plot of NHANES FEV1% MalesGOLD applies a value of 70% for the value of FEV1 as a percent of FVC to define airflow limitation. All major prediction equations find that FEV1% falls with age and so the LLN for this index also drops with age. The Figure opposite shows a theoretical sample population of men whose data fit the NHANES III [ 12 ] equation for FEV1%. All subjects plotted as green dots are truly within the normal range. Those plotted in red are below the LLN and represent the expected 5% of the total population (vide supra). The light blue dots are those subjects where GOLD falsely says they are normal (>70%) but are in fact below the LLN (false negatives) and the mid blue dots are those where GOLD says they are abnormal when in fact they are above the LLN (false positives).

Plot of NHANES FEV1% FemalesWhen considering a similar plot for females in the Figure opposite it can be seen that the age at which the 70% cutoff changes from giving false negatives (light blue) to false positives (mid blue) in women is about 50 yrs and is older than that found in men, approx 40 yrs.

Thus not only does the GOLD criterion of <70% for FEV1% falsely categorise subjects it also introduces a sex bias.

Plot of ECCS FEV1 data for womenTo the right is the same plot as above but for females, and it can be seen that the age where false positives start is again older in the females, and now there are some subjects that GOLD says are normal (light blue dots) but who are in fact below the LLN and so are false negatives.

Conclusions

The GOLD criteria were set up in 1997 in an attempt to standardise the future research into COPD so that all workers in the field could work to a common standard. There was insufficient evidence at the time to substantiate the rules that were presented. In the light of current evidence it is clear that the main crux of diagnosis of COPD by the GOLD criteria are flawed.

This will lead to more older subjects being diagnosed with COPD than is justified, since the inclusion criteria as shown above will include a significant number of normal subjects who do not have disease, as well as lead to false negative findings in younger subjects [ 5-11 ]. These false positives will then possibly receive treatment and unnecessary tests they do not require and bear the burden of the label of disease they do not warrant.

It is clear that the scientific community in Respiratory Medicine move to correct this anomaly so that research into COPD is not contaminated by the rules being wrong at the start.

 

Added Sept. 10, 2009:
The GOLD Guidelines [1], which originally recommended a FEV1/FVC ratio below 0.70 as indicative of obstructive lung disease, now state:

“…because the process of aging does affect lung volumes the use of a fixed ratio may result in over diagnosis of COPD in the elderly, especially of mild disease. Using the lower limit of normal (LLN) values for FEV1/FVC, that are based on the normal distribution and classify the bottom 5% of the healthy population as abnormal, is one way to minimize the potential misclassification”

In keeping with the ATS and ERS recommendations, in order to avoid over diagnosing (and therefore over treating) elderly patients, and under diagnosing younger patients, the GOLD guidelines state that:

“…many experts recommend use of the lower limit of normal for each population”.

References

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Additional references that advocate the use of the lower limit of normal and/or reject a fixed FEV1/FVC ratio

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See also: Expressing test results

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