Establishing Normal Reference Values in Quantitative Computed Tomography of Emphysema

Quantitative computed tomography (QCT) can provide reliable and valid measures of lung structure and volumes. Similar to lung function measured by spirometry, lung measures obtained by QCT vary by demographic and anthropomorphic factors including sex, race/ethnicity, and height in asymptomatic nonsmokers. Hence, accounting for these factors is necessary to define abnormal from normal QCT values. Prediction equations for QCT may be derived from a sample of asymptomatic individuals to estimate reference values. This review article describes the methodology of reference equation development using, as an example, quantitative densitometry to detect pulmonary emphysema. The process described is generalizable to other QCT measures, including lung volumes, airway dimensions, and gas-trapping. Pulmonary emphysema is defined morphologically by airspace enlargement with alveolar wall destruction and has been shown to correlate with low lung attenuation estimated by QCT. Deriving reference values for a normal quantity of low lung attenuation requires 3 steps. First, criteria that define normal must be established. Second, variables for inclusion must be selected on the basis of an understanding of subject-specific, scanner-specific, and protocol-specific factors that influence lung attenuation. Finally, a reference sample of normal individuals must be selected that is representative of the population in which QCT will be used to detect pulmonary emphysema. Sources of bias and confounding inherent to reference values are also discussed. Reference equation development is a multistep process that can define normal values for QCT measures such as lung attenuation. Normative reference values will increase the utility of QCT in both research and clinical practice.