7. 医学筛查_做，还是不做

Chin Med J 2010;123(14):1948-1951 1948 Viewpoint Medical screening: to be or not to be? WANG Wei-zhong and TANG Jin-ling Keywords: medical screening; benefits; harms; cost WHAT IS MEDICAL SCREENING? Worldwide chronic diseases have become a major cause of suffering, disability and mortality. When patients are diagnosed as a result of the appearance of symptoms, it is often too late and treatment options are limited. Hoping that early diagnosis and early treatment can retard or stop disease progression, medical screening is proposed as a secondary prevention method in which people without specific medical complaints are invited to undergo interventions to identify and modify risk factors, or to find disease early in its course so that early treatment prevents further severe complications.1,2 Screening can be defined as “the systematic application of a test, or inquiry, to identify individuals at sufficient risk of a specific disorder to warrant further investigation or direct preventive action, amongst persons who have not sought medical attention on account of symptoms of that disorder.”3 In fact, what is screened for could be either a disease or a risk factor for an important disease. The purpose of screening is secondary prevention of more severe complications in the former case and primary prevention in the later case. For example, a skin test called the PPD is widely used to screen for exposure to tuberculosis,4 mammography to detect breast cancer,5 colonoscopy to detect colorectal cancer,6 and cholesterol screening to find a high risk population for coronary heart disease.7 Screening should not be taken as just application of a test. Figure 1 uses Papanicolau (Pap) smear for screening cervical cancer to show the general flow and main components of a screening program. Figure 1. An example of medical screening: Pap smear to detect in situ cervical cancer. Early diagnosis and early treatment incur costs and do harm but may not necessarily lead to a greater benefit. Useful screening programs are those that can bring about more good than harm at an acceptable cost. What screening programs would be potentially useful? WHEN WOULD SCREENING BE POTENTIALLY BENEFICIAL? Major factors related to the potential usefulness of a screening program include the disease, the screening test and the treatment. Disease The disease to be screened for must have a long detectable preclinical phase. The severity of the disease must be considered a large disease burden to the population in terms of suffering, disability, destitution and death, and the pre-clinical phase of the disease must be relatively prevalent. The preclinical or asymptomatic phase of a disease is the time period from the onset of the disease to the time that symptoms appear and a diagnosis is made by a doctor. A long pre-clinical phase is the prerequisite for the disease to be detected and treated early enough for the treatment to be more effective. Most infectious and acute diseases that have a very short asymptomatic phase are not suitable for screening, while cancers that may have a preclinical period of many years are often the target of screening. Although the burden of disease is a relative concept, diseases such as cancer that cause suffering, disability, and death are generally more suitable for screening than illnesses such as minor skin problems. The prevalence determines the total number of cases that can be detected by screening. If too few cases are detected, no matter how effective the treatment would be, screening would not have an important impact on the disease burden.8 The prevalence of a disease is positively DOI: 10.3760/cma.j.issn.0366-6999.2010.14.022 Department of Administration and Logistics Management, Institute of Pathogen Biology, Chinese Academy of Medical Sciences, Beijing 100730, China (Wang WZ) Division of Epidemiology, School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China (Tang JL) Correspondence to: Prof. TANG Jin-ling, Division of Epidemiology, School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China (Tel: 852-22528779. Fax: 852-26063500. Email: jltang@cuhk.edu.hk) Chinese Medical Journal 2010;123(14):1948-1951 1949 related to the prevalence of the risk factors and the average duration of the preclinical phase. The prevalence of the undiagnosed but detectable preclinical disease also depends on whether or not the population has been screened previously. Recent screening of a population would reduce the number of undiagnosed asymptomatic patients. This suggests that in order for the screening program to be cost-effective, two subsequent rounds of testing should not be done too close. For example, in breast cancer screening the test should be performed again in the same person every 3–5 years rather than very year. Screening test The screening test refers to the test or a series of tests used in a screening program to identify those who are likely to have the disease and warrant further confirmatory diagnostic investigations. Screening is feasible only if a good screening test is available. The test should be sufficiently accurate, i.e., it should have desirable sensitivity and specificity. The ability of a test to classify people who truly have the pre-clinical disease as test positive is sensitivity. The ability to classify those who are truly free of the disease as test negative is specificity. If sensitivity and specificity are not perfect (which is almost always the case in screening), errors will occur in the test. Those who truly have the disease but are test negative are false negatives; false negative results would lead to missing the opportunity of early diagnosis and treatment. On the other hand, those who are truly free of the disease but test positive are false positives; false positive results would cause unnecessary confirmatory diagnostic investigations and even unnecessary treatments. Moreover, the screening test should be able to give sufficient lead-time. Lead time is the time period from the time an asymptomatic patient is detected by screening to the hypothetical time point when symptoms would appear and diagnosis would be made by a doctor if the screening test had not been performed. For a group of patients this lead time can be estimated but for any individual patient lead time is always a hypothetical concept and un-estimable. For a screening program to be effective in reducing morbidity and mortality in a population there must be enough lead time in a sufficient number of cases. If lead time is insufficient, cases may not be treated in time to retard or stop the progression of disease. The test should also be simple, rapid, inexpensive, and safe so that it can be applied to a large number of people at an affordable cost and people and physicians will be willing to do the testing.9-11 Screening can not be either too expensive to be affordable or too unattractive so that people will not do it. The test should be easy to learn and perform. These that can be administered by non-physician medical personnel will necessarily cost less than those that need to be performed by a doctor of years of medical experience. Moreover, screening that requires hospitalization of people for a few days to go through complex and invasive procedures are unlikely to be very much welcomed by either doctors or patients. Treatment If screening can bring about any good, it will be from the treatment rather than any other activities of a screening programme. Therefore, for a screening program to be potentially beneficial there must be treatments available that are effective and acceptable to asymptomatic patients. Treatments used for late-stage patients do not necessarily help early-stage patients, nor would treatments acceptable to symptomatic patients be equally acceptable to asymptomatic ones. How do we know whether early treatment would lead to better outcomes than late treatment? For cancer screening, early attempts to evaluate the outcome of screening compare the survival rate at various time points after treatment between asymptomatic cases detected by screening and symptomatic cases diagnosed due to symptoms. A higher survival rate in patients detected by screening would suggest that screening could reduce the death rate and increase survival. However, this comparison is flawed and the results often mislead. The major biases include lead time bias, length bias and selection bias. Due to lead time bias, patients detected by screening would necessarily survive longer than those diagnosed due to symptoms simply because the former patients were diagnosed earlier (by the amount of lead time) than the later in the natural history of the disease. This is true even if early detection and early treatment do not affect the natural progress of the disease at all and early detected patients would live as long as the patients diagnosed due to symptoms after the onset of the disease (Figure 2A). Length bias occurs because the same cancer may progress at a different rate in different patients (Figure 2B). Screening tests are likely to find tumors with a moderate growth rate (type B patients), whereas fast-growing tumors (type A patients) would cause symptoms and be diagnosed by a doctor before screening and slow-growing tumors (type C patients) are too small to be detectable at the time of testing. Screening, therefore, tends to find tumors with inherently better prognoses than those found by doctors. As a result, the survival in patients detected by screening would be better than those diagnosed due to symptoms even if screening is ineffective. Selection bias occurs because not everyone will participate in a screening program and those who do participate may differ from those who do not. If people at a higher risk of the disease are more eager to be screened, for instance, women with a family history of breast Chin Med J 2010;123(14):1948-1951 1950 Figure 2. The major biases. A: Lead time bias. Dx is the time of diagnosis; the light shaded area is the survival after diagnosis if there is no treatment or treatment is ineffective; the dark shaded area is the extra survival due to effective treatment. Type A patient represents those normally diagnosed and treated without screening. Types B and C patients represent those early detected and treated and only Type C patient represents those who has a real benefit from screening. The comparison of type A patients with types B and C patients is biased by the lead time which is unknown in real patients so that we cannot distinguish between situations respectively represented by types B and C patients. Thus, we can not tell whether screening is beneficial or not by such comparisons. B: Length bias. Rapidly growing tumors (A) will develop symptoms and diagnosed by a doctor before screening is performed, slowly growing tumors (C) are too small to be detectable at the time of testing, and only tumors at a medium-growth rate (B) can be detected by screening. As a result, comparison of type A patients with type B patients will be biased as type B patients are bound to survive longer than type A patients even if screening is not effective. cancer are more willing to get a mammography, a screening test will look worse than it truly is. This will cause selection bias in the above comparison. Conversely, selection bias can make screening look better than it truly is. If the test is more available to the young and healthy, for instance, if people have to travel a long distance to be screened, fewer people in the screened population would die than those who do not participate and screening would seem to make a positive difference. The reliable method to evaluate the effectiveness of a screening program is a cluster randomized controlled trial, in which groups or communities are randomly allocated to receive either screening or normal care without screening. A lower mortality from the screened disease in the screened group than the control group will suggest screening is beneficial. For example, randomized controlled trials show that mammography can significantly reduce mortality from breast cancer in women over 50 years old.12 In contrast, chest X-rays with or without sputum cytology do not affect mortality from lung cancer.13 BENEFITS, HARMS AND COSTS OF SCREENING Screening offers a benefit at a cost. The costs include money and time incurred, and inconvenience, worries and harm to the screened. Benefit Screening can be effective only when the detected patients can be effectively treated. The size of the benefit from a screening program will be determined by the total number of cases detected and the effectiveness of the treatment. The former is further determined by the prevalence of the disease and the sensitivity of the test. The higher the prevalence and the sensitivity are, the larger number of cases will be detected and then treated. The total years of life gained from screening is the product of the number of cases treated and the extra survival gained due to early treatment compared to late treatment. If the treatment is effective, the benefit can be increased by screening only persons at a high risk of disease, by using a test of high sensitivity, by using a cutoff value that gives rise to a high sensitivity, and/or by testing the same persons less often. Cost Costs are incurred for the initial test, for the confirmatory diagnostic investigations, and for treating the detected patients. The first two costs are necessary and can not be avoided, whereas confirmatory diagnostic investigations are where a high unnecessary cost may occur. These investigations are normally much more expensive and more time-consuming per person, and more likely to be invasive and cause harms than the initial test. For people whose tests are false positive, these investigations are unnecessary and should be reduced to a minimum. The false positive rate is determined by the specificity of the test and the prevalence of the disease. The lower the prevalence and the specificity are, the higher the false positive rate will be. As the prevalence is mostly low in screening, the main method to reduce the cost due to false positives is to increase the specificity of the initial test. However, sensitivity and specificity of a test are inversely related and an increase in specificity will inevitably decrease sensitivity, which determines the number of cases detected and consequently the benefit. Therefore, a good screening program must carefully choose the test and determine the cutoff value for the test so as to achieve a desirable combination of sensitivity and specificity. This will help favorably balance the benefit against the cost and harm. Harm Harms in screening are mainly in the following forms: harm and inconvenience caused by the initial test; negative labeling effects (stress and anxiety caused by a false positive result); harm and inconvenience caused by unnecessary investigations in false positive patients; harm, inconvenience and costs incurred in unnecessary treatment of those who do not have the disease or have Chinese Medical Journal 2010;123(14):1948-1951 1951 the disease that would never progress to the clinical stage and would not have been treated if there were no screening; prolonged stress and anxiety if detected patients can not be effectively treated; a false sense of security caused by false negative results which could delay final diagnosis. Unnecessary harm comes mainly from false positive results. TO SCREEN OR NOT TO SCREEN? All screening programs incur cost and do harm; only some have good as well. Only screening programs that can do more good than harm are useful. For similar reasons, periodic health checkups, which are probably less scrutinized and more widely adopted, should be evaluated in a similar manner. The benefit of screening can only be reliably demonstrated by a randomized controlled trial. Even if effective, only a few people will eventually benefit from it at a large cost to the society. Even worse, the harm starts immediately but the good, if any, takes longer to appear. Thus, the decision to introduce a new screening program should be made as carefully as the decision to build a large new hospital. When would the benefit from a screening program be worth its costs and harm? The answer to this question would inevitably vary across populations that have different resources available and different health needs to address. In order to achieve good value for money from screening, developing countries should screen only when there a desirable benefit:harm ratio, where “desirable” is not universal but determined by the resources available locally and the values of the population. The cost-benefit ratio can be further improved by targeting people at a high risk of the disease, by performing the test when people visit physicians for other illnesses, by testing less often, and/or by using a test with a high specificity. REFERENCES 1. Eddy DM. Common screening tests. Philadelphia: American College of Physicians; 1991: 7-10. 2. Morabia A, Zhang FF. History of medical screening: from concepts to action. Postgrad Med J 2004; 80: 463-469. 3. National Screening Committee. First report of the National Screening Committee. London: Health Departments of the United Kingdom; 1998 (Accessed June 5, 2010 at http://www.nsc.nhs.uk/pdfs/nsc_firstreport.pdf). 4. American Thoracic Society. 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Cochrane AL, Holland WW. Validation of screening procedures. Br Med Bull 1971; 27: 3-8. 12. Wells J. Mammography and the politics of randomized controlled trials. BMJ 1998; 317: 1224-1230. 13. Bach PB, Kelley MJ, Tate RC, McCrory DC. Screening for lung cancer: a review of the current literature. Chest 2003; 123: 72-82. (Received February 3, 2010) Edited By SUN Jing