False-negative Results in Screening Programmes Systematic Review of Impact and Implications
Abstract
"Screening is the systematic application of a examination or inquiry, to place individuals at sufficient take a chance of a specific disorder to do good from farther investigation or direct preventive activity, amid persons who have non sought medical attention on account of symptoms of that disorder."1
- screening
- cancer
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- screening
- cancer
Early detection and intervention is intuitively attractive, particularly for cancer when the consequences of illness may be serious and information technology seems obvious that early detection must be beneficial. Wilson and Jungner in 1968two proposed a set of criteria for assessing whether screening is worthwhile and their carefully reasoned and considered approach has served public health well in the post-obit decades. Now, with several decades of screening experience to draw on, we suggest the post-obit criteria (1 to iii below) need to be considered in assessing whether screening is worthwhile. In addition one farther, rapidly developing issue (four below) needs urgent debate and research. These points are identified below and and then briefly discussed.
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Cancer screening programmes should no longer exist introduced without evidence from randomised trials demonstrating a mortality benefit or a quality of life benefit (for case, need for less invasive treatment)
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The extent of inconsequential disease that will be generated by the screening program should be estimated and carefully considered earlier widespread introduction of screening
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The benefit (demonstrated by trials) should exist weighed against the harms of screening to assess whether in that location is likely to be a internet do good from screening before widespread introduction of screening
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If screening is introduced, potential participants in the screening plan should be given information that allows them to weigh up the probable benefit and harms, using their own values and preferences
EVIDENCE
Assessing the bloodshed or quality of life benefits of cancer screening is, in itself, a circuitous exercise. The all-time level of evidence comes from randomised trials, which may randomise participants to screening or non-screening arms (equally for case in trials of mammographic screening),3 or may randomise screen detected cases to early versus later treatment (every bit for example in trials of cholesterol screening).4, 5 Information technology is important that randomised trials of screening run into quality criteria for randomised trials in general (that is, there should exist allotment concealment, blind cess of outcomes, small losses to follow upward, and analysis by intention to care for).6 In addition trials of screening need to avoid lead time bias by using appropriate upshot measures such every bit the mortality rates in both arms of the trial (and not survival time from diagnosis as this will probably consequence in lead fourth dimension bias). While trials of screening should be critically appraised (and may exist found wanting every bit in the recent controversy over the analysis of mammographic screening trials by Olsen and Gotzsche7), they remain the best level of show to establish the benefit of early on detection and treatment.
An insistence on randomised trials of screening may exist regarded by some as unreasonable. Simply decisions that accept the potential to affect hundreds of thousands (or millions) of people and that will place large burdens on healthcare resources, as population screening programmes inevitably practise, must be based on the best possible evidence. Furthermore, there is an ethical imperative to base interventions that will exist conducted on asymptomatic people on the best possible bear witness because of the potential to harm those who are well, for example by psychological or physical adverse effects of investigations conducted on people who receive imitation positive screening test results.
INCONSEQUENTIAL Affliction
Screening can lead to widespread over-detection and over-handling of inconsequential disease. Screening for cervical cancer and for prostate cancer both frequently detect depression course disease that is unlikely to ever become symptomatic in screening participants' lifetimes. Inconsequential illness has also been chosen "pathologists' disease" (with apologies to pathologists) because there is histological evidence of affliction, just the changes are low course and unlikely to progress to invasive, symptomatic disease. For example, in cervical cancer screening abnormal smear tests are diagnosed in "6800 of every 100 000 women screened when the annual incidence of invasive cervical cancer in England and Wales was never greater than 30 per 100 000".8 Clearly this represents enormous over detection and, considering no ane can tell which cases will progress, enormous over treatment of cervical intraepithelial abnormalities. The costs of inconsequential disease may exist enormous, both for individuals and for the health budgets of countries that introduce cancer screening programmes.
WEIGHING UP BENEFITS AND HARMS
If a clear benefit of screening is demonstrable in randomised trials, the harms of screening demand to be weighed against that benefit and an assessment made of whether in that location is likely to be a net benefit of screening. Harms include psychological and physical agin furnishings of follow up tests, equally well every bit the effects of inconsequential affliction. Balance sheets of the consequences of screening are urgently needed (see tabular array ane for an example). Assessments of the ratio of true positive: false positive results when new screening tests are proposed may also exist useful in weighing benefit against harms.
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Table 1
Anticipated outcomes of ten years of biennial mammographic screening of 10000 Australian women from 40 years of historic period
Private VALUES AND PREFERENCES
Traditionally public information about screening has been aimed at achieving high uptakes, rather than informed choice10– xiii and individual values are usually ignored for the sake of achieving population benefits from screening. Still when benefits and harms are finely counterbalanced, individuals' preferences are likely to be of import in deciding whether there is internet benefit or net harm for an individual participant. It may well be that two people considering, for instance, colorectal cancer screening may come to opposite only informed and rational views as to whether screening is worthwhile for them. It seems that there is a business organization that a reduction in uptake and therefore in population benefits volition occur with full disclosure of the benefit and risks associated with screening programmes. This provides a tension with the guidelines from the General Medical Council that make it clear that full information almost the benefit, risks, and consequences of screening should be provided to potential participants. At the same time it needs to be recognised that the way information about the benefits and harms of screening is presented is important and there are concerns that those most likely to exist deterred from screening may be the most socially disadvantaged.10
The following glossary is intended to provide a framework for reading research on screening for cancer and to stimulate give-and-take on the points raised above. The terms are presented in groups of terms with related meanings rather than alphabetically.
TARGET CONDITION
The target condition in this context refers to cancer or loftier form abnormality that is likely to progress to cancer within a specified fourth dimension frame (months to a few years). We consider depression grade abnormalities that are unlikely to progress to cancer, such every bit low grade squamous intraepithelial lesions in programme screening for cervical cancer, to exist imitation positives or nuisance positives (see Fake positive and Inconsequential illness).
BENEFITS OF SCREENING
Accurate early on diagnosis of cancer (or pre-cancer) gives the opportunity to start handling earlier illness progresses, thus potentially reducing the need for aggressive therapy, reducing the likelihood of metastatic disease, and averting cancer deaths. The size of the benefit depends on the effectiveness of early intervention compared with intervention at the time when the target condition is expected to manifest clinically. Reassurance afforded past a normal consequence may too be considered a do good, although it is difficult to see reassurance as a benefit if the public was unaware of the target condition earlier the introduction of a screening programme.
HARMS OF SCREENING
For those who receive an abnormal test result, harms of screening may include complications arising from early investigation and treatment, unnecessary treatment of people with inconsequential disease, and unnecessary investigations of those who receive false positive results.4 In improver, adverse psychological furnishings of labelling or early diagnosis, anxiety, and the costs and inconvenience incurred are besides potential harms. A negative result may give false reassurance and potentially cause a delayed presentation of symptomatic disease.14 This is true for both false negatives (when disease is present but currently undetected), and for true negatives (if affliction develops after the screening examination and the reassurance afforded past the previous negative test results in delayed clinical presentation).
Residue SHEET
A tabular array outlining the consequences of screening (for example, per yard or per 10 000 people screened). The numbers of people who experience the do good(s) and harm(s) of screening are provided to assist people to make up one's mind whether they consider screening is worthwhile.xv Encounter table 1 for an case.
INCONSEQUENTIAL Disease
A disease state that is detected by screening only that would not contribute to a poor consequence if undetected by screening. An case is low class prostate cancer detected by screening, but that, without screening, would not have get symptomatic in the man's lifetime.
SCREENING INTERVAL
The period of time between each screening round.
INTERVAL CANCER
An interval cancer is a cancer that is diagnosed subsequently a normal screening test event was given and earlier the next scheduled screening test or during some defined time period later the screening test. Interval cancers include a spectrum of cancers, from those that either did not be or were undetectable at the previous screening round to those that were detectable but missed.16 While this theoretical distinction exists, in practice it can be difficult to dissever accurately the "missed" cancers (or imitation negative results) from cancers that either did not be or were undetectable at the previous screen.17
INFORMED PARTICIPATION
Rates of participation (or screening uptake rates) are the proportion of those eligible for screening who are actually screened. High participation rates have been considered an of import mensurate of programme success every bit higher participation rates should be associated with greater population benefit. Yet, the potential do good that the individual participant can look is non affected past the participation (or non-participation) of others. Once the programme is established, the price effectiveness should not be greatly afflicted by participation rates as costs and benefits will tend to increase proportionally as participation rates rise.18 Thus at that place is increasing debate nearly whether the programmes should be judged by their participation rate or by their capacity to provide for informed choice and informed participation.10 To achieve informed pick, information about the purpose of screening, including information on bloodshed reduction with screening, the likelihood of positive and negative findings (including faux negative and simulated positive results), uncertainties and risks of screening, important medical, social or fiscal consequences of screening, and follow upwardly plans should exist given.nineteen Screening determination aids may exist useful for this purpose.
FALSE NEGATIVE
A normal (negative) examination event in a person who has the target condition.
FALSE POSITIVE
An abnormal (positive) test event in a person who does non have the target condition. The false positive rate (the proportion of unaffected individuals identified as positive through screening), or 1−specificity, is important in quantifying the number of people without the cancer who volition demand farther investigation. A reduction in the false positive charge per unit is usually but achieved at the expense of a greater fake negative rate. The relative weight given to the test thresholds that are chosen for recall and follow upwards should ideally reflect the implications of false negative and simulated positive results and the values ascribed to these implications by participants. Increasingly, it is being suggested that we consider the cumulative false positive rate of a screening programme as we are unremarkably repeating the screening test over a number of years at a recommended interval between tests.20
SENSITIVITY (TRUE POSITIVE OR DETECTION RATE* OF A SCREENING TEST)
The proportion of individuals who take the target condition who receive a positive (abnormal) test outcome. A screening test that is more sensitive volition pick up a greater proportion of those with the target condition and thus make a favourable divergence to issue when early intervention is effective. However, information technology is possible that a more sensitive test may worsen the trade off between benefits and harms if the exam picks up more than cases of inconsequential disease.
SPECIFICITY (TRUE NEGATIVE RATE OF A SCREENING TEST)
The proportion of individuals free of the cancer in a population who are correctly identified past a screening test as being free of the cancer. If a new screening test is more specific (results in fewer false positive results) then the potential impairment of screening may be reduced.
POSITIVE PREDICTIVE VALUE (OF A SCREENING Test)
The proportion of individuals with an aberrant test upshot who have the target condition. An culling term, the "odds of beingness afflicted given a positive result" (OAPR) is the ratio of true positives to simulated positives.one
INTENTION TO SCREEN Assay/PRINCIPLE
In a trial of a screening intervention, patient outcomes are analysed co-ordinate to the grouping to which subjects were randomised, irrespective of whether those in the screening and control arms actually participated in screening. The importance of this principle lies in ensuring that randomisation is preserved, thus maintaining an equal distribution of important factors that may influence the outcome in the control and intervention groups. Using intention to screen analysis also reflects more closely the population benefit that can be expected given participation rates that are likely to exist encountered in practice. If desired, an aligning can exist made to de-benumb the effect of less than 100% participation to provide an gauge of the likely do good for those people who do actually attend for screening.21
SOJOURN Fourth dimension
The elapsing of the period in which the target condition is asymptomatic merely detectable past screening.22 Sojourn fourth dimension is too chosen the preclinical duration or preclinical stage.
Pb TIME BIAS (Zero Fourth dimension SHIFT)
Pb time is the flow of time between the detection of the target condition by screening and the time when the condition would have been diagnosed clinically (if screening had not occurred). In effect screening brings forward in fourth dimension the diagnosis, giving people more than fourth dimension to live knowing their diagnosis (in other words more than "illness time"). Screening may therefore seem constructive (even if ineffective) if survival from time of diagnosis is used as the upshot to compare screen detected cases with clinically diagnosed cases. This is called lead time bias.
LENGTH Time BIAS
People whose disease is discovered by screening may also seem to live longer as screening tends to detect slowly progressing disease and may miss chop-chop progressing disease that becomes symptomatic between screening rounds.23 Thus, a comparison of survival among screen detected cases compared with clinically diagnosed cases may show an apparent benefit of screening even if screening is ineffective (length fourth dimension bias).
RELATIVE RISK REDUCTION (RRR)
The difference in consequence rates between control and intervention groups, divided past upshot rate in control group, or 1−relative adventure (RR). This measure out is used when the upshot of interest is an adverse consequence and the intervention reduces the chance.
ABSOLUTE Gamble REDUCTION (ARR)
The divergence in event rates between control and intervention groups. The value of the accented gamble reduction depends on the baseline gamble of affliction and thus can present a more realistic estimate of the size of the bloodshed benefit24 than the relative risk reduction.
NUMBER NEEDED TO SCREEN (NNS)
In the case of a randomised trial of screening (in which participants are randomised to screening or to no screening), the reciprocal of the ARR is the number needed to screen (NNS) to prevent one adverse outcome. Recently it has been suggested the term NNS should be adjusted for participation charge per unit and that this be known equally the NNBS—number needed to be screened.25 The number of people who really need to participate in screening to prevent one decease is lower than the number of people who demand to be invited to screen to foreclose one death; therefore, NNBS figures are normally lower than the NNS. Every bit NNS is based on absolute take a chance, making comparisons between screening programmes using NNS may be misleading if there are differences in the baseline risks of weather condition beingness compared.26
REFERENCES
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