CT screening for lung CA: an epidemiology primer

Amid the hype surrounding it, there is an opportunity to ponder the new NCI CT screening study that reduced lung CA deaths by 20% over the 5-year follow-up. The study itself was interesting, as it was a randomized controlled trial of the screening. This means that, although the possibility of lead time bias remains as the explanation for some of the detected difference (this refers to the fact that in the CT scan group the cancers were diagnosed earlier and therefore the deaths may still occur but simply beyond the five-year follow-up period), this is less likely than in any other design. So, the findings, while intriguing, need to be considered with the modicum of caution as recommended by the NCI, particularly given the high number needed to screen to save one life (300), and the high number of false positives requiring invasive testing. Not to mention all the radiation exposure.

So, while the analyses of the trial continue, some groups, such as the Steelworkers' Union, have already jumped on the side of demanding screening for their members. Is this altogether unreasonable and premature? Well, while it may be premature, I do not think that it is altogether unreasonable. And this has to do with screening test characteristics, some of which are immutable and others exquisitely dependent on the population being screened.

The test characteristics that tell us how well a test detects disease are sensitivity, specificity, predictive positive value and predictive negative value. Sensitivity refers to how well the test picks up the disease that is really there, while specificity tells us whether we can trust that a positive test signifies the presence of the particular disease in question. We also calculate a positive predictive value (PPV, or how much we can trust that a positive test really signifies the presence of the disease), and a negative predictive value (NPV, or how sure are we that a negative test result really means the absence of the disease).

In epidemiology, where we are always concerned with denominators, we like to construct so-called 2x2 tables to illustrate. Here is an example:  

 
The values in the squares signify the following: A = true positives, B = false positives, C = false negatives, D = true negatives.

And while both sensitivity and specificity of a test are intrinsic characteristics of the test itself and are not subject to change by the population risk of the disease, not so for PPV and NPV. These measures are sensitive to the pre-test probability of the disease being present. That is, the PPV and NPV of a test are enhanced if the population is enriched for persons with a higher likelihood of the disease.

This brings me to the Steelworkers' Union demand for CT screening. Here is their rationale:

"Millions of workers have been exposed to asbestos, silica, chromium, arsenic, beryllium, cadmium, nickel and combustion products — and all of these exposures are firmly established as causes of human lung cancer.

Union health and safety leaders and others need to meet in the very near future in Washington DC to devise a strategy for assuring that high risk workers are among the first to obtain the benefits of this new screening method."

And here is why it is not altogether unreasonable. Now, it is well appreciated that these workers have high rates of smoking. According to the CDC, smoking alone increases the risk of lung cancer 10-20-fold. It is also well appreciated that occupational exposure to asbestos, for example, is associated with an enormous increase in the risk of lung cancer. More importantly, however, together with smoking these exposures gang up as a team to help each other to promote cancer much more effectively than if each were working alone. This is called potentiation, and it results in a multiplicative increase in lung cancer risk when both smoking and occupational exposure exist. Therefore, the population represented by the Steelworkers' Union is indeed enriched for the risk of lung cancer development, and may indeed be the population where both the PPV and the NPV are enhanced beyond what we see in smokers only. This means a higher degree of certainty that a positive CT finding truly represents cancer, as well as increased comfort that a negative test is not simply missing a cancer that is there. As a corollary, this means a potentially optimized risk-benefit balance for this screening test.

So, while we are awaiting further data from the trial, the Steelworkers' Union may be on to something.