From the Department of Epidemiology, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, WA.
Received for publication April 17, 2002; accepted for publication October 17, 2002.
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ABSTRACT |
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confounding factors (epidemiology); effect modifiers (epidemiology); neoplasms
Abbreviations: Abbreviation: NSAID, nonsteroidal antiinflammatory drug.
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INTRODUCTION |
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In at least some parts of the world, it is now relatively common for screening to be done for cancers of the mouth, esophagus, stomach, colon and rectum, lung, breast, prostate, and cervix and for melanoma. The presence of such screening can influence studies of the etiologies of these cancers in at least two ways. First, to the extent that the introduction of screening in a population (or its cessation) affects the actual or reported incidence of the cancer, it can interfere with the interpretation of comparisons of incidence by place and time. Second, in some circumstances a history of screening can act as a confounder in cohort and case-control studies of that cancer. The purpose of this commentary is to characterize those circumstances and to describe the aspects of the subjects screening histories for which control of confounding is desirable.
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HOW CAN FAILURE TO CONSIDER SCREENING HISTORY DISTORT OUR ASSESSMENT OF AN EXPOSURES POSSIBLE INFLUENCE ON CANCER INCIDENCE? |
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With regard to a possible association between screening history and cancer incidence, at least one of the following conditions needs to be fulfilled before it would be appropriate to treat screening history as a confounder.
Condition 1
The screening modality has the potential to identify not only the cancer per se but also the treatable antecedents of the cancer. Although the available screening modalities for cervical or colon cancer can reveal the presence of invasive cancer, most of these also have the potential to detect premalignant conditions (intraepithelial neoplasia and adenomatous polyps, respectively) whose treatment can lead to a reduction in cancer incidence (1, 2). So, for example, in a study of use of nonsteroidal antiinflammatory drugs (NSAIDs) in relation to the incidence of colon cancer, adjustment for a history of colon cancer screening would be needed to yield a valid result if NSAID use were found to be associated with screening. If a relatively higher proportion of users of NSAIDs had received screening during the period of time in which the premalignant condition is detectable prior to its malignant degeneration, a negative association would be observed between NSAID use and colon cancer incidence even in the absence of any true antineoplastic action of these drugs. In contrast to this example, consider a hypothetical study of NSAID use and prostate cancer. Screening for prostate cancer, by means of a digital rectal examination or the measurement of prostate-specific antigen levels in serum, can detect the presence of prostate cancer itself, but not any precursor lesions. Since screening is unable to lead to the prevention of prostate cancer occurrence, in order for it to act as a confounder the next condition would have to be met.
Condition 2
The number of cases included in the study would have been smaller but for the presence of screening.
Etiologic studies of cancer antecedents
Often, the pathologic changes in a tissue that can later give rise to malignancy will be detectable only by means of screening. This is true for cervical preneoplasia, which would not be identified in the absence of a Papanicolaou smear or the application of some other cervical screening modality. Most case-control studies of cervical preneoplasia have sought to control for potential confounding by restricting controls to women who have been screened as negative (3, 4). During investigation of exposures that themselves are related to the likelihood or frequency of being screened (use and type of contraception, perhaps), this approach is sound: If a study of cervical preneoplasia fails to select cases and controls who are comparable with regard to a history of screening during the period of time the preneoplastic condition is presumed to be detectable, the study will not be able to separate potential risk factors for receipt of screening from those for the presence of the condition itself.
Etiologic studies of cancer
Apart from those instances in which screening identifies premalignant changes whose successful treatment averts the development of some cancers, screening does not have the capacity to cause or prevent cancer. Nonetheless, the observed incidence of cancer in a population over a given period of time can be substantially influenced by the level of early detection activity. This can occur for two reasons.
First, a test identifies some lesions that are labeled as cancer but that truly do not have malignant potential. Among endometrial hyperplasias that develop in postmenopausal women who take unopposed estrogens, it is likely that some are misdiagnosed as cancer when an endometrial biopsy is performed in response to estrogen-induced uterine bleeding (5). The distinction between endometrial hyperplasia and cancer can be subtle, and pathologists differ regarding the criteria they use for distinguishing the two conditions. In studies of the relation of estrogen use to risk of endometrial cancer, this nondifferential misclassification of disease status (false positives particularly occurring among hormone users) likely is responsible for a portion of the observed excess risk. As another example, there is reason to believe that screening for what is typically a very aggressive malignancy, lung cancer, can uncover some lesions that though labeled as cancer, in actuality do not have the potential to cause death. The existence of these cases of "pseudodisease" (6) has been deduced from data gathered in randomized trials of intensive screening for lung cancer by means of chest radiographs and sputum cytology (7). These trials have not observed a reduction in the mortality rate from lung cancer compared with a regimen of less intensive screening, even though the case fatality after more than 20 years of follow-up among persons diagnosed with lung cancer is relatively smaller in intensively screened persons (8).
Even if a screen-detected lesion truly does have malignant potential, if the lesion fails to manifest that potential for an extended period of time, the person harboring it may die from other causes before it is detected. This is likely the situation for a number of screen-detected prostate cancers in older men: Some of these lesions are indolent enough that death from coronary disease, stroke, and so on would take place before the cancer could produce symptoms or signs sufficient to lead to its diagnosis in the absence of screening.
Second, the use of the screening test in the population under study is not constant over time. During the follow-up interval of a cohort study or the intake period of a case-control study, screening will give rise to the recognition of cancer in some persons who would otherwise not have been diagnosed until later, after that period had ended. If the level of screening in the base population for the study were higher during the period of case accrual than it had been previously, there would be more screen-detected cases "gained" from the subsequent period than would be "lost" to the preceding one. Overall, there would be more cases in the study than if screening had not been on the rise, and each of the "excess" cases would be positive for a history of screening.
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FOR WHICH ASPECT OF A STUDY SUBJECTS SCREENING HISTORY SHOULD WE CONTROL? |
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THROUGH WHAT MEANS SHOULD POTENTIAL CONFOUNDING BY SCREENING HISTORY BE CONTROLLED? |
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MISCLASSIFICATION OF SCREENING STATUS |
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Unfortunately, in these studies there is considerable opportunity for differential misclassification of screening status as well. Many of the same tests used to screen for the presence of cancer are also administered as part of the diagnostic evaluation of persons with signs or symptoms of cancer, and medical records may not capture the distinction. For example, consider a positive prostate-specific antigen test done in an asymptomatic man who has just had a prostatic nodule detected on a digital rectal examination. Even if the presence of the nodule had been noted in the record, the status of the prostate-specific antigen test would depend on whether or not it would have been done irrespective of the result of the digital examination: "diagnostic" if done only in response to the presence of the nodule or "screening" if it would have been performed in any event. However, the intent of the provider of care in situations like this often is unknown, and such tests cannot be unambiguously classified as "screening" or not.
Since a far greater proportion of persons with cancer than persons without cancer will have tests done in response to signs or symptoms of that condition, the potential for misclassification of these as screening tests particularly affects the former group. An example of the impact of differential misclassification of this sort on the results of an epidemiologic study of cancer is illustrated in table 1. The upper portion contains hypothetical data from a case-control study in which screening status has been ascertained without error. A history of one or more screens during the presumed preclinical detectable period was more common among cases than controls and also more common among the exposed than the nonexposed. Thus, even though the odds ratio within each of the two strata based on screening history was 2.0, the crude odds ratio relating exposure and disease was 2.33.
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Even when the screening histories of study participants are obtained without error, residual confounding can be present when we restrict or adjust for screening status if we misestimate the interval during which screening history is relevant for the potential detection of early cancers or precancers. In practice, it would be desirable to see if the size of the association between exposure and cancer incidence is sensitive to changes in the width of that interval. Residual confounding also can be present if the exposure has a bearing on the sensitivity of screening. For example, use of hormone therapy by postmenopausal women often leads to increased mammographic density, diminishing the ability of the screening modality to identify breast tumors (13). In this instance, adjustment for the fact of screening during the 2 years prior to diagnosis of breast cancer, for example, will not remove all possible confounding by differences in the receipt of effective screening between hormone users and nonusers.
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IS IT DESIRABLE TO CONTROL FOR THE RECEIPT OF TESTS PERFORMED IN RESPONSE TO SIGNS OR SYMPTOMS OF THE CANCER? |
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Unfortunately, in this instance, this was probably not the case: Women who undergo endometrial biopsy generally do so for uterine bleeding, which is a much more common result of hormone therapy than the development of cancer. In this case-control study, a substantial amount of selection bias likely was present, in that the proportion of hormone users in the controls likely was considerably in excess of the proportion among women in the population at risk of endometrial cancer. This example serves to warn us that, while control for receipt of screening is often desirable to control confounding in epidemiologic studies of cancer, control for receipt of diagnostic testing can produce misleading results and should be undertaken only with great caution. Bias due to misclassification of disease generally can be dealt with in other ways, such as by conducting analyses in which cases are restricted to persons whose tumor is unequivocally malignant.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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