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Bias due to the use of % predicted for spirometric indices in adults

Let us consider the following two males:

Predicted FEV1
Observed FEV1

In the youngest of the two, according to the rule of thumb‘ that over 80% of predicted is within normal limits’ an FEV1 of 4.10 liter would be regarded as satisfactory; it should be noted, however, that such a value occurs in only about 4% (z-score -1.70) of healthy subjects. In the elderly man an FEV1 of 2.25 L would have been regarded as abnormally low, whereas this would be frequently observed in a population of healthy subjects. An analogous situation occurs in women.

This problem may also affect scientific projects. Just consider this example:

assess the effect of drug X on FEV1 in patients with airway obstruction
double blind intervention trial of drug X and placebo
subjects with airway obstruction defined as FEV1< 80% predicted
on average the effect of drug X is smaller in the elderly subjects than in young patients
the ‘reversibility’ of airflow limitation is less in elderly subjects, which appears plausible to you; the drug is less effective in elderly subjects

Use of FEV1%predicted leads to biased resultsComments: due to the ’80% predicted criterion’ each group comprises elderly and short subjects who in effect do not have airway obstruction, whilst younger and taller subjects with mild airway obstruction have been eliminated by the selection strategy. Who knows the conclusion might have been the same had a more correct selection criterion been used, but the present selection criterion introduced a bias towards overrepresentation of elderly and short subjects and underrepresentation of young subjects into the material which may (at least in part) explain the findings.

One can graphically depict the ‘lower limit of normal’ based on either a fixed percentage (e.g. 80%) of the predicted value, or the 5th percentile. Each criterion may lead to different conclusions for the same subject, and this varies with age and standing height, but also with gender and ethnic group.

In keeping with this Hardie et al. [1] reported how the application of the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria for defining stage I of COPD (FEV1%FVC < 70% and FEV1 % predicted > 80% leads to 35% of healthy, elderly nonsmoking subjects being wrongly classified as having COPD stage I. In those aged > 80 yrs this increased to 50%, and approximately one-third would be classified as having stage II COPD.
Such results, as explained above, are perfectly predictable and arise from the arbitrary and unscientific definition of cut-off criteria. Such criteria do the patient no good at all and potentially lead to over-diagnosis and over-treatment. The latter is only of benefit to the pharmaceutical industry.

1. Hardie JA, Buist AS, Vollmer WM, Ellingsen I, Bakke PS, Mokve O. Risk of over-diagnosis of COPD in asymptomatic elderly never-smokers. Eur Respir J 2002; 20: 1117-1122.

See also: Letter to the members of the GOLD committee.

GOLD COPD stage 1 does not represent lung disease

  1. Ekberg-Aronsson M, Pehrsson K, Nilsson JA, Nilsson PM, Löfdahl CG. Mortality in GOLD stages of COPD and its dependence on symptoms of chronic bronchitis. Respir Res 2005; 6: 98.
  2. Bridevaux P-O, Gerbase MW, Probst-Hensch NM, Schindler C, Gaspoz JM, Rochat T. Long-term decline in lung function, utilisation of care and quality of life in modified GOLD stage 1 COPD. Thorax 2008; 63: 768 - 774.
  3. Vaz Fragoso CA, Concato J, McAvay G, et al. Chronic obstructive pulmonary disease in older persons: a comparison of two spirometric definitions. Respir Med 2010; 104: 1189 - 1196.
  4. Vaz Fragoso CA, Concato J, McAvay G, et al. The ratio of FEV1 to FVC as a basis for establishing chronic pulmonarydisease. Am J Respir CritCare Med 2010; 181: 446-451.
  5. Pedone C, Scarlata S, Sorino C, Forastiere F, Bellia V, Antonelli Incalzi R. Does mild COPD affect prognosis in the elderly? BMC Pulm Med 2010; 10: 35.
  6. Vaz Fragoso C, Gill T, McAvay G, et al. Use of lambda-mu-sigma-derived Z score for evaluating respiratory impairment in middle-aged persons. Respir Care 2011; 56:  1771-1777.
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