Genetic Screening Research Paper

2. Definition

Genetic screening is the application of a test on people for the systematic early detection or exclusion of a hereditary disease, a genetic predisposition to a disease, or to determine whether a person carries a predisposition which may produce a hereditary disease in their offspring (Health Council of the Netherlands 1994). Testing is not restricted to the study of DNA or chromosomes, but includes the use of any test which is designed to detect and exclude hereditary disease, predisposition, or carrier state. Early detection means that the testing is applied to those who have not ( yet) sought medical aid because of physical signs, symptoms, or anxiety. So it is typically the care system that takes the initiative. The word ‘systematic’ in the definition implies that screening is offered to all people in a predefined target group, e.g., neonates or pregnant women.

2.1 Terminology

Genetic screening shares its terminology with epidemiology and genetics. A test result is called positive when it points to the presence of the feature sought after. Similarly, a result is said to be negative when it indicates the absence of the feature. Both results, however, may be true or false. A test result, for instance, is called false positive if it indicates that the feature looked for is present while in reality it is absent. The probability that a certain test result is true or false depends on the prevalence of the feature and two test characteristics: sensitivity and specificity. Sensitivity refers to the proportion of cases in which the presence of the feature is identified by the test. Specificity is the proportion of cases in which the absence of the feature is correctly identified by the test. The predictive value of a test result, either positive or negative, indicates how often that test result is correct. As to the terminology of genetics the reader is referred to other articles. An exception is made for the term ‘penetrance.’ Penetrance is the frequency of cases in which a particular genotype comes to expression.

3. Characteristics Of Genetic Screening

As with other types of medical screening, diagnostic confirmation of a positive screening test is an integral part of the screening procedure. Unlike other types of screening, however, genetic screening looks for stable characteristics of the participants. So in general, once an individual is tested, repetition of the test is not needed. In screening for infectious diseases or cancer, the majority of participants, namely the true negatives, the false positives, and the cured, have to return for subsequent testing after a set time period.

The stability of the genetic characteristics also makes it possible to predict disease long before it would become manifest without intervention. In principle this lead time (time until disease becomes manifest) can be lifelong, or with prenatal diagnosis even longer. It is clear that this is an unwanted situation unless interventive measures are more effective when they are started early.

A further characteristic of genetic screening that differentiates it from other types of medical screening is that a positive test result may frequently have consequences for the family members. This does not apply to all types of genetic screening. For instance, finding a fetus with a regular trisomy 21 Down syndrome does not increase the risk for sisters of the pregnant woman, since this is a spontaneous mutation. But finding through screening that someone carries, for example, two mutations of the gene involved in hemochromatosis puts his or her siblings immediately at a 25 percent risk of having the same mutations (Worwood 2000). They may be grateful to know this since manifestations of this iron overloading disease can be prevented effectively by regular bleeding, but the point here is that one’s decision to participate in a genetic screening program is to some extent a decision involving family members who might have preferred to make such choices themselves.

4. Target Groups

The target groups for genetic screening may consist of individuals or couples. Screening newborns for phenylketonuria (PKU) or young adults for hemochromatosis are examples where the individual is the target. In both cases the goal of identifying these persons is to offer timely intervention (dietary measures prevent the development of mental retardation in PKU, and bleeding prevents the iron overloading in hemochromatosis). Other examples are screening for other inborn errors of metabolism, congenital hypothyroidism (CHT), and familial hypercholesterolemia.

Screening for carrier status of autosomal recessive diseases such as cystic fibrosis, thalassemia, and TaySachs disease can be offered to individuals, but because being a carrier is only significant when the partner is a carrier too, screening for carrier status can also wait until a partner has been found and reproductive issues arise. In this case the couple rather than the individual is the target. When both partners of a couple are carriers (for the same disease) their children are at 25 percent risk for the disorder.

Screening during pregnancy may be targeted at characteristics of one to three individuals. First, the fetus may be studied directly, for instance when ultrasound is used for the detection of congenital anomalies in general or nuchal translucency (an indication for the existence of Down’s syndrome) in particular. Second, the screening may involve the pregnant woman first, such as is the case with maternal serum screening, e.g., triple test. In case of a positive test result the fetus becomes involved in a definitive diagnosis. Third, both the pregnant woman, her partner, and the fetus may become involved. This is the case with couple screening in pregnancy.

4.1 Timing

As hinted at above, apart from determining who should be screened, it is important to define the best moment for screening within the lifetime of the individual or couple. The earliest possibility is preimplantation genetic screening (PGS) in case of in vitro fertilization (IVF). With pre-implantation genetic diagnosis (PGD), one is looking for a disorder for which this particular embryo has a particular high risk, while in PGS the embryo at stake has a not much higher risk than other pre-implantation or IVF embryos. PGS for chromosomal anomalies, for instance, would be very helpful to select the embryos with the highest chance of survival.

Prenatal screening, newborn screening, and adult screening are discussed above. Some people advocate screening in high school. Couple screening can be performed premaritally, preconceptionaly, and prenatally. Premarital screening is perhaps the best choice in cultures where selection of marriage partners is done by third parties, without involving the partners at all. Compulsory premarital screening, after the partners have matched, as is the case for thalassemia in Cyprus, infringes personal autonomy. Preconceptional screening is characterized by difficulties of reaching the target group in time. So the majority of couplescreening programs target pregnant women (and their partners).

4.2 Taking Advantage Of Family Structure

Cascade screening is a special type of genetic screening. Starting from an individual with the characteristic of interest (the proband), one offers screening to his or her first-degree relatives. Once the relatives with the same characteristic have been identified, their firstdegree relatives are also offered screening, and so on. This type of screening is suitable for dominant disorders, such as familial hypercholesterolemia, and for X-linked disorders with high penetrance and low mutation rate. It has, however, also been proposed for the detection of couples who are carriers of an autosomal recessive disease such as cystic fibrosis. The disadvantage there is that only a small proportion of at-risk couples can be identified in this way. So, screening without taking the family structure into account is a better option. A combination of noncascade and cascade screening may, however, be very efficient.

4.3 Other Technicalities

In many cases it is not possible or feasible to have a test which is 100 percent sensitive or specific. The lack of perfect specificity can be countered by subsequent diagnostic workup. When the screening involves a DNA test, specificity is usually very high. If in the cascade approach family members are tested for the same mutation as has been found in the proband, sensitivity is also very high. In case of a test with imperfect sensitivity (e.g., 90 percent), the imperfection is multiplied in couple screening (81 percent).

Couple screening has many modalities (ten Kate et al. 1996). One may test one partner first, and only if this first partner tests positive, test the other partner (single entry or step-wise screening), or one may test both partners always (double entry). One may also decide to screen partners of carriers for more mutations than is feasible in the initial screen. One may sample both partners simultaneously or stepwise. One may give complete results, or only tell the couple whether they are both carriers or not.

5. Psychosocial Impact Of Genetic Screening

The purpose of genetic screening is to provide people with information about their risks and the options available to them to avoid the birth of an affected child or to take preventive measures in case of a serious disease. Genetic screening seems especially advantageous when intervention measures are available. For instance, for women with a high risk of hereditary breast cancer, confirmation that they are carriers makes it possible for them to take preventive measures such as participating in an intensive screening program for early detection of the disease. Because the potential impact of genetic screening is considerable, the advantages as well as the disadvantages of genetic screening should be considered carefully before deciding to offer a specific screening program routinely.

The availability of genetic screening may also have its drawbacks. Although the available choices would appear to increase people’s control over their own destiny, they are actually experienced by many as an additional burden. An indication of the perceived difficulty of decisions is the finding that although most people at risk for a genetic disease say they intended to be tested in the future, many are not (e.g., Lerman et al. 1996). Some people might prefer the uncertainty of not knowing above the certainty that, for instance, they will develop a serious disease for which there is no cure, such as Huntington’s disease. In addition, with the increasing possibilities and availability of genetic screening, more and more people, some with a very low risk for chromosomal abnormalities who first did not consider screening, are now confronted with the choice to undergo screening. In many countries young pregnant women with a low risk of having a child with Down’s syndrome are offered prenatal screening. If they choose screening, they must cope with the possibility of a positive screening result and the implication that confirmation is needed with invasive diagnostics such as amniocentesis that itself carries a risk of miscarriage. When they decide against screening, they must deal with the feelings that they could have done otherwise in case things turn out badly and the child is affected.

The decision for or against screening is not only complicated emotionally but also cognitively. Genetic risk information is complex and replete with uncertainties, associated not only with the hereditary nature of the disease but also with (un)informativeness of the test results, the effectiveness of preventive measures, and the variability of expression of the disease (incomplete penetrance). For example, when a woman is diagnosed as ‘at risk’ for breast cancer based on family history, there is only a 30 percent chance that DNA testing will result in a conclusive test result. If a woman is a carrier of the breast cancer gene, she has an increased risk of getting breast cancer: 7 out of 10 women who are carriers will get breast cancer before the age of 75, and 3 of them even before 40. There is a 3 in 10 chance, however, that a woman who is a carrier will not get breast cancer. This is complicated information and difficult to integrate to make the decision about testing (e.g., Bottorff et al. 1998). Providing information about genetic risks of, e.g., breast cancer is considered an important component of genetic education and genetic counseling. The importance attributed to risk information is illustrated by the fact that recall of risk information and understanding of probabilities are considered central measures of the effectiveness of genetic counseling. The underlying assumption that accurate perception of risk could help people to make informed and individual decisions seems to be based on the principle of the autonomous and rational decision maker. From this perspective the most important goal of genetic education and counseling is to provide people with all relevant information in an understandable way. It is therefore important to find the best format to communicate risks and to stimulate a rational tradeoff of pros and cons of several options. Research has shown, however, that people find it difficult to understand risks and to make rational tradeoffs. It has been shown that knowledge of actual population risks of, e.g., breast cancer is far from adequate. People either underestimate or overestimate the risk and often fail to make a distinction between the population risk and their own risk. Genetic counseling has been shown to improve accurate risk perception, although the majority of women still have an inaccurate perception after counseling (e.g., Cull et al. 1999).

In the case of screening for a hereditary disease, the decision to screen is complicated by the potential impact that test results could have on family members. As has been pointed out, genetic screening may have implications for family members and may put familial relationships under pressure. For example, one sister may want to know more about the hereditariness of breast cancer while another sister might prefer not to know. The same goes for couples when there is no agreement as to whether to test for carrier status for, e.g., cystic fibrosis.

If the decision is made and test results become available, these need to be interpreted. Mostly, test results also involve uncertainties. A positive test result after prenatal screening for Down’s syndrome means that the risk of having a child with Down’s syndrome is higher than 1 in 250. A decision then must be made whether or not to confirm this chance estimate with invasive diagnostics whereby the extra information must be traded off against the risk of a miscarriage. Screening and waiting for the results have an emotional impact on people. Receiving test results, whether they are positive or negative, is also emotionally stressful. Many low-risk people are likely to undergo testing for reassurance and hope for a good result. Most of them will receive a negative test result. For those who perceive themselves as being at risk this is reassuring, but the news will perhaps be learned at the expense of knowing that they were at risk in the first place. It has been shown that anxiety exists even after negative results of prenatal screening (Green and Statham 1996). Learning what could go wrong without the possibility of ruling out all possible defects makes women more aware of birth defects and affects their sense of vulnerability. Testing for carrier status of cystic fibrosis involves a large number of mutations but it is practicable to test only for the most common. If tested negative, the carrier status of cystic fibrosis, therefore, cannot be ruled out completely and no complete reassurance can be given that one is not a carrier. Even if testing implies that the person is not at risk, some members of risk families for, e.g., Huntington’s disease find it difficult to cope with a future that no longer includes the expectation of getting a serious disease. An explanation for these negative feelings after being tested negative is that being at risk for this serious disease was part of one’s identity which then needs to be changed (Tibben et al. 1997).

A positive screening test is obviously upsetting even if it turns out to be false. Women having diagnostic tests as a result of a positive screening test have been shown to be especially anxious compared to women who chose amniocentesis directly. Most of these women will be shown not to carry a child with Down’s syndrome, and their anxiety can be considered to be unnecessary. Testing positive as a carrier of a recessive disease such as cystic fibrosis without actually having the disease can affect one’s view of and one’s optimism about the future. Being identified as a carrier for a genetic disease may affect how an individual perceives him or herself and how he or she is perceived by others. Being tested positive for a disease for which there is no cure (such as Huntington’s disease) also affects one’s view on the future. Because nothing can be done to prevent the disease, this knowledge will not be considered as useful by all people (Keenen 1996). As more genetic conditions become diagnosed before any cure is in sight, more and more individuals will be added to the at-risk pool many years before a cure is possible. Some people may even be at risk their whole life for a condition they will never develop. It is therefore important to determine for which conditions and for whom genetic testing should be available.

It could be argued that at the basis of many of the problems or possible negative effects of genetic screening described above is a poor understanding of genetics, the tests, and the meaning of test results. It is therefore very important that the public as well as people with an at-risk status learn more about genetics, what it means to have some abnormal genes, how best to make a decision, what it means to have a positive screening result, etc. Professionals should learn the best way to provide genetic information in such a way that people can make a balanced decision for or against genetic screening and be able to cope with the test results so that the advantages of screening will be maximized and the disadvantages minimized (Schwartz et al. 1999).

6. Criteria

There are many genetic, medically relevant characteristics for which, in theory, screening could be started now. There will be many, many more in the future. It is quite clear that it is not desirable to screen for all these characteristics, and careful selection is needed. Apart from potential benefit, potential harm should be considered. Harm could be physical, psychological, social, or otherwise. Not only the effects of screening on the participants should be taken into account, but also the effects on nonparticipants.

Many individuals and groups have worked on the development of criteria that should be fulfilled for screening in general (EUROGAPPP PROJECT 1999–2000, Holtzman and Watson 1997, Nuffield Council on Bioethics 1993). Some countries have also developed specific legislation. It is widely recognized that every individual screening program should be tested to see if it reaches appropriate standards.

Basically, the information that is needed for this test can be grouped into three sets. The first set concerns what is known about the disease or characteristic and about the screening program (state of knowledge). The second set concerns the advantages and disadvantages arising from the screening, and the third set is about the guarantee of autonomous decision.

The disease should be well delineated. Its general course should be clear but also the amount of variability in its course. The effects of intervention should be known. A reliable test should be available with known sensitivity, specificity, and predictive value. The screening program should be described in detail, including the availability of intervention and follow-up. Privacy protection, and permanent quality control of all aspects of the program should be ensured.

Practical courses of action should be available for the participants, such as preventive measures or reproductive choices. The psychological and social effects should be known for the participants and nonparticipants in general, but also and in particular for those among the participants who are faced with a positive test and those among the nonparticipants who are confronted with the disease in themselves or in a child. Also, more remote effects on society should be considered, e.g., on the amount of support for handicapped people. Finally, the financial costs of the program should be taken into account and alternative strategies to combat the health problem should be considered. All this information should make it possible to compare and weigh the benefits and drawbacks of the program. The final balance should be clearly biased towards the benefits.

Participation in the screening program should be voluntary and based on good-quality information and informed consent. People should be given enough time to reach a balanced decision. This requirement may be difficult to realize in prenatal and neonatal screening, but every effort should be made to inform pregnant women about the decision to come as early in pregnancy as possible. People should have ample opportunities for pre-test consultation. People should not be taken by surprise (as in opportunistic screening).

It is desirable to have an authority to supervise all (genetic) screening programs in a country or larger region. Criteria should be the same for screening programs offered by nonprofit organizations and commercial firms. As more and more tests become available, problems inherent in multiple testing arise. Multiple testing increases the frequency of false negative and false positive results and augment the difficulty of giving sufficient information to reach a balanced decision.

The complexity of genetic screening makes it a multidisciplinary area, involving medical doctors, laboratory specialists, epidemiologists, psychologists, sociologists, jurists, ethicists, patient organizations, and representatives of the community.

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