Genetic Screening Research Paper

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Advances in technology, especially DNA sequencing, have greatly increased the potential capacity of genetic screening in public health programs. In contrast to the reactive nature of most health professional activities, where professionals respond to the preexisting concerns of their patients, in screening it is the professionals who are proactive in approaching individuals who, until that point, have regarded themselves as “healthy” or “well”: the goal is to identify latent disease or future risk of disease. This is usually performed on population subgroups (often based on age, gender, and ethnicity). Screening programs include newborn, antenatal, carrier status, and disease susceptibility screening. The scope of screening has extended from the use of relatively simple and inexpensive screening tests for highly treatable conditions to a complex and diverse range of program screening for rare disorders or using complex algorithms to infer clinically relevant information, as with fetal DNA in maternal plasma.

Long-established screening criteria are being challenged by the increased capacities of laboratory systems, especially the use of high throughput DNA sequencing. This blurs the formerly fairly clear distinction between reactive, diagnostic testing and proactive screening tests. This distinction breaks down when genome-wide methods are employed as the favored laboratory method in the diagnostic assessment of a wide range of disorders. The test being used in a diagnostic process yields up information that is incidental to the diagnostic question, so that the diagnostic test has now become also a genomewide screening test.

This research paper examines the recent history of screening criteria and summarizes the ethical issues related to genetic and genomic screening.

Introduction (Brief Outline)

Screening is the process through which clinical information and/or laboratory tests are used in the examination of asymptomatic individuals with the aim of detecting disease, predisposition to disease, or factors – biochemical, molecular, or lifestyle – that can increase the risk of a disease occurring. Testing for genetic disorders may involve a molecular genetic test – for a specific mutation or a disease-associated variant – or a cytogenetic investigation for chromosome number or composition. It may also involve other, nongenetic modalities of investigation, perhaps biochemical (for metabolic or muscle disease) or imaging (e.g., for renal anomalies or fetal malformation). Screening for predisposition and screening for complications of a genetic disorder may blur into one another, as when genetic testing is used to determine entry to a program of screening for malignancy in those at increased risk. When discussing screening, it is essential to define what is being proposed or discussed with clarity and precision, as the scope for confusion is substantial.

Genetic screening involves testing an individual for the genetic change (mutation) underlying a condition or abnormality that may be suggested by other evidence, for example, having signs or symptoms of a particular disease or having an affected relative. Usually, this follows consultation with a medical practitioner or genetic counselor who, having established disease risk, would support individuals through the testing and results process. Genetic screening differs as it involves testing members of a population (or subpopulation) for a mutation where there is no prior evidence of disease or increased disease risk in the individual being screened, or their relatives. Such testing usually takes place as part of a public health service, for example, the screening of (effectively) all newborn infants for phenylketonuria (PKU). Alternatively, screening may be limited to a subpopulation at particular risk (a “target population”) of a genetic condition. This risk may relate to ethnicity – for example, carrier testing for Tays-Sachs disease among Ashkenazi Jews – or to pregnant women and the risk factors for fetal aneuploidy or malformation, including maternal age, biochemical or endocrine markers in maternal serum, and the findings on fetal ultrasound scan (Human Genetics Commission 2006).

Genetic screening can involve genetic or nongenetic technologies. The use of genetic tests can identify individual DNA changes that cause or are associated with disease in a given population. Alternatively, nongenetic technologies can give indirect information about genetic anomalies. Thus, biochemical tests such as tandem mass spectroscopy used in newborn screening can identify metabolic abnormalities that result from underlying genetic disease. When increased risk is identified, further confirmatory testing may be carried out to confirm (or refute) the diagnosis. As screening is usually carried out without prior knowledge or evidence of a disease being present, the ethical issues are different from those arising in the genetic testing of at-risk individuals. In most health service encounters it is the patient who approaches the professional because of a concern. In screening, it is the professional who approaches the asymptomatic individual to offer screening, which may thereby trigger concern and anxiety.

History And Development (Background)

Wilson and Jungner first attempted to define the criteria against which proposed population

screening should be evaluated in 1968 (Wilson and Jungner 1968). At this time, technical advances in medicine made screening a topic of increasing importance yet also of significant practical and ethical challenge. Wilson and Junglier identified ten criteria to be considered in making decisions about screening programs:

  1. The condition sought should be an important health problem.
  2. There should be an accepted treatment for patients with recognized disease.
  3. Facilities for diagnosis and treatment should be available.
  4. There should be a recognizable latent or early symptomatic stage.
  5. There should be a suitable test or examination.
  6. The test should be acceptable to the population.
  7. The natural history of the condition including development from latent to declared disease should be adequately understood.
  8. There should be an agreed policy on whom to treat as patients.
  9. The cost of case finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole.
  10. Case finding should be a continuing process and not a “once and for all” project.

These classical screening criteria emphasized the importance of evaluating screening targets against rigorous criteria, recognizing the potential negative impact of widespread, poorly evidenced screening. Criteria included the magnitude of the health problem and the availability of effective therapies that could substantially alter the disease course only if introduced before symptoms were recognized, alongside the need for the acceptability of the proposed test to both public and professionals.

While “in theory, screening is an admirable method of combating disease … in practice, there are snags” (Wilson and Jungner 1968), particularly when screening is performed by “.. . a public health agency, where the pitfalls may be more numerous than when screening is performed by a personal physician.” With respect to the use of genetic testing in such screening, the “snags” concern how the availability of new technologies creates pressure to introduce and expand screening programs before the evidence of benefit is well established and before safeguards or regulatory frameworks can be agreed.

The early screening programs to be introduced were newborn screening programs for phenylketonuria and then congenital hypothyroidism; antenatal screening for neural tube defects and, later, Down syndrome; and carrier screening for betathalassaemia, sickle cell disease, and Tay-Sachs disease. These programs have met the accepted criteria for screening. Since then, however, the Wilson and Jungner criteria have been challenged by two developments: (i) broader conceptions of the benefits of screening for particular disorders and (ii) technological developments that have enabled the extension of screening to large diagnostic categories of disease almost as easily as to a single disorder, so that the whole process of making decisions about screening one disease at a time – disease by disease – has been challenged. This has led to efforts to refine the criteria for screening (Andermann et al. 2008).

The ten reworked criteria for screening are similar to the original set but are subtly different:

  1. The screening programs should respond to a recognized need.
  2. The objective of screening should be defined at the outset.
  3. There should be a defined target population.
  4. There should be scientific evidence of screening program effectiveness.
  5. The program should integrate education, testing, clinical services, and program management.
  6. There should be quality assurance, with the mechanisms to minimize potential risks of screening.
  7. The program should ensure informed choice, confidentiality, and respect for autonomy.
  8. The program should promote equity and access to screening for the entire target population.
  9. Program evaluation should be planned from the outset.
  10. The overall benefits of screening should outweigh the harm.

The changes in emphasis seek to address some of the concerns surrounding the use of genetic technologies in population screening, in particular, the need for evidence as to how the test functions in practice, the effectiveness of the program as a whole, and the need for consent to testing, which itself requires that those deciding whether to participate have sufficient information about the implications – the meaning – of a positive or a negative screening test result, in addition to the capacity to make a decision and freedom from external pressure.

While many of the screening programs’ established aim is to detect genetic disorders, this has often not employed genetic technologies in the initial screening but only in a secondary step closer to the point of diagnosis. Thus chromosome testing for Down syndrome has usually been employed in antenatal screening for chromosome anomalies only in those pregnancies where biochemical or imaging evidence indicates an increased probability of Down syndrome; similarly, conventional newborn screening for cystic fibrosis employs molecular genetic tests to identify mutations in the CFTR gene only in infants whose serum trypsin levels are raised. However, the decreasing cost and increasing speed of “next generation sequencing” (NGS) will often enable the introduction of DNA sequencing as the primary screening modality. This greatly amplifies the information that can be obtained from screening and therefore correspondingly amplifies the scope and scale of the potential social and ethical concerns raised by population genetic screening.

Ethical Dimension

Utilitarian and libertarian perspectives each provide a lens through which to look at the bioethical considerations surrounding genetic screening. Utilitarian approaches have much in common with the core notion of public health ethics: moral decisions with regard to the ratio of (potential) burden and benefit are best made from a societal perspective, with the promotion of societal good being of greater importance than the net effect on any single individual. When multiple people are at risk of a particular disease, all are informed of the risk, and invited to participate in screening (the “target population”), which can decrease the probability that the risk will occur, delay symptom onset, increase quality of life through timely changes to lifestyle, and enable informed reproductive decisions. In this sense, maximizing health and well-being is seen as an individual responsibility supported through participation in public health measures, such as population screening. Individuals autonomously participate in screening, with autonomy (autosself, nomosrule or law) employed in a sense closer to its original meaning, pertaining to the governance of people within cities, rather than the vernacular of independence and individuality. This respect for the collective aspect of “autonomy,” implicit in the original usage of the word, mirrors the collective nature of genetic and genomic information, as belonging to families rather than individuals. The “communitarian turn” (Chadwick 2011) in bioethics has shifted emphasis onto principles of solidarity, equity, and public good. In the genetic context, this perspective allows us to both acknowledge and address the challenge facing informed consent for genetic testing as insufficient, or inadequate, in performing all the ethical work. If family members are not told of possible harm, the principles of nonmaleficence and justice are violated.

Libertarian perspectives prioritize autonomy as the highest moral value, centralizing the need for individual decision-making based on personal needs and concerns. Such perspectives have been seen as at odds with population-focused and utilitarian approaches, where the core expectation is that individuals will consent to and undergo recommended screening for both personal and familial reasons and for the broader societal good. As such, libertarian perspectives prioritize the right to know, alongside the well-established right not to know genetic information. This recognizes that genetic information from screening may carry a significant burden in itself or in practical terms of additional screening to be undertaken, or the expectation of compliance with prophylactic interventions and presymptomatic treatments and the making of difficult reproductive decisions, both for the individual and the family. This recognition of the possible harms of screening is supported by appeal to the principle of nonmaleficence, with libertarians concluding that individuals have the right to be happy and make health and reproductive choices free from the influences of medical or public health professionals, fearing the possible discrimination or social isolation such results might entail.

Principles such as nonmaleficence can be subject to different interpretation depending on whether we use the expressed wishes of the individual undergoing testing, their “best interests” as decided clinically, or the best interests of the wider family network as determined by the utilitarian calculator. Individuals have a right not to know their genetic status for a particular disorder: telling them in this case contravenes the principle of autonomy and perhaps also nonmaleficence, if it causes harm as well as affront. However, knowing about one’s status may also decrease stress, leading to a beneficent outcome. The different ethical perspectives will inspire different courses of action, but all can be expressed in the language of principles, framed to reflect the chosen perspective.

Why Is Genetic Screening Ethically Challenging?

Genetic screening involves considerable ethical challenges.

Consent And Pretest Counseling

Ethical practice involves seeking consent from patients for any investigation or intervention undertaken – individuals must be allowed to make autonomous decisions about investigations they undergo based on their own wishes or values and given their knowledge of the proposed screening and of their individual circumstances. The question of “consent” then raises several questions of interaction in clinical practice: should the practitioner take on trust that each patient has thought the issues through and applied their values to making their decision, or should they offer to explore the issues with the patient and even perhaps challenge the patient to think through the potential implications of a decision to accept or to decline screening? How much knowledge about the screening program, and how thorough an understanding, are necessary for consent to be accepted as adequately informed? The danger of setting too high a standard of knowledge and understanding is that many might be excluded from participation if they were either unable or unwilling to engage with the details of the screening program.

In screening that relates to reproduction, the patient’s values may frequently differ from those of the practitioner or health service, being either more insistent on “quality control” of any prospective child or completely opposed to the idea of such screening and wishing to accept and embrace any child they have conceived.

In genetic screening for susceptibility to disease, the screening is likely to be offered commercially as the benefits of most genetic screening investigations for the patient’s health are uncertain, with no clear clinical utility established for the direct-to-consumer (DTC) panels of tests so far available. These would therefore not be made available through regular healthcare channels that implement evidencebased practice. Consent is therefore obtained in an active sense because screening is a purchase. However, the validity of the consent may be in doubt because of the poor evidence base used to justify the screening. There have been interesting legal developments in USA where the Food and Drug Administration has challenged DTC corporations (including 23andMe) to justify their claims for the validity and utility of their services. These challenges have led to these corporations choosing to close their services (within USA) rather than rising to the challenge. The utility of exome or whole genome sequencing as an approach to population screening to guide “healthcare for the healthy” remains to be established, although this is likely to be introduced before long. At present these technologies are mostly being applied to patients who are unwell, either with a malignancy or with an undiagnosed and often rare disorder.

Consent for newborn screening is of course a proxy consent granted by parents, where consent is required for newborn screening. Newborn screening is not available globally, so in some countries or areas it is optional (and private) while in others it is mandatory. In some states within the USA, newborn screening does not require parental consent and is “mandated” so as to ensure equity of access, with the admirable aim of universal access to newborn screening. While there are valid grounds for declining other screening programs, such as cultural or religious reasons, these do not generally apply to screening for newborn infants, which is aimed very largely at interventions for the direct benefit of each infant. As such, a degree of parental involvement in decision-making is compromised in light of the perceived benefits of newborn screening in terms of health outcomes for the infant and the consideration of justice in ensuring that these benefits are accessed by as many individuals as possible. In other states, newborn screening requires parental consent, and in these states there is active promotion of informed participation through parental education.

In the UK and other European countries, consent for screening must be “adequately informed” (Nuffield Council on Bioethics 2006) meaning individuals undergoing testing must be able to understand the reasons for, consequences of, and alternatives to participating in screening. However, what constitutes “adequately informed” remains contentious. In light of the full range of possible outcomes, particularly where genomic technologies are employed, provision of informed consent is challenging. The consequences of screening outcomes can be highly variable, including the diagnosis of unexpected disease, the inadvertent identification of carrier status for autosomal recessive disease, and the potential implications of false-positive diagnoses that may require investigation and potentially unnecessary treatments. For genetic conditions, the implications for the health and reproductive decisions of relatives may also be an important consideration. There is a need for a balance between providing adequate information for a sufficient understanding while not compromising informed decision-making through information overload, particularly where genetic screening is applied on a population level.


For genetic screening to provide maximum population benefit, when disease or disease risk, is identified, all at-risk individuals must be informed and supported in accessing appropriate management, which may include further investigations, providing the opportunity for treatment, prophylaxis, enhanced screening for complications, and informed, autonomous decision-making about reproduction. The potential need for the sharing of genetic information within the family should be communicated prior to screening, and the obligation of medical professionals to act in the best interests of families by initiating cascade testing. In undertaking screening, the emphasis is on population-level approaches, rather than individual, so that participation in screening can be framed as a personal recognition and approval of this approach. This clearly differs from the stricter norms of confidentiality in the traditional doctorpatient relationship within the medical consultation.

False Positive And Negative Results

Another important consideration in populationlevel screening is the need to balance the benefits for certain individuals of accurately identifying disease versus the harms for others associated with false-positive screening results (when screening identifies disease or risk of disease which is not present). False-positive results can be a source of anxiety and uncertainty, requiring additional medical investigations with their associated risks and also potential early treatment or lifestyle modification while diagnoses are confirmed or excluded. When the benefits of early detection of disease are well established and evidenced, such risks can be more easily counteracted than when expected benefits are modest, or poorly evidenced at population level.

How to generate and present the evidence of the program’s sensitivity (the proportion of individuals with disease who are correctly identified by the test) and specificity (the proportion of disease-free individuals who are correctly identified as such) is not absolute; instead it is dependent on the expected benefits of detection. High specificity is of greater importance when the diagnosis is associated with significant anxiety or stigma or when confirmatory diagnostic tests are associated with significant risks, discomfort, cost, and time. Similarly, when cases are likely to be detected by other means and while effective treatments are still available, specificity is a priority. This is contrasted with a preference of high sensitivity, which is important when adverse consequences of a missed diagnosis risk serious harm or death. Here, beneficence may outweigh nonmaleficence as the key guiding principle.

In addition to sensitivity and specificity, however, it is also most important that the participants in a screening program have some appreciation of the positive and negative predictive values of the test. These are the chance that a positive screening test corresponds to a true positive diagnosis and the chance that a negative screening result corresponds to the absence of the disorder. These figures are most important for participants to understand, especially once they have been given their result, as they indicate the limitations of the screening test. These figures are related to but distinct from the sensitivity and specificity of the screening test and are relatively neglected compared to the sensitivity and specificity.

The consequences of false-positive identification can be very significant in this context. The promotion of an “opportunistic genomic screening” strategy in the USA is leading to the active disclosure to patients of many unsought results, unrelated to the indication for the genomic investigations. Unless patients have explicitly opted out, samples undergoing whole genome sequencing for any clinical indication are also screened for pathogenic mutation in 57 well-evidenced, disease-associated genes (Green et al. 2013). Kingsmore used Bayesian probability to look at the potential implications of this methodology, summarizing with this considered perspective: “..the pretest probability of a true positive result in a disease gene that fits the symptoms of an ill child is high. In this setting, false-positive results are uncommon and there is usually physician and family support for further confirmatory tests to weed out the few that do occur. In contrast, the pretest probability of a true positive result in these 57 genes in the general US population is less than 1 in 1000. In this setting, there are likely to be 20 false-positive results per true positive” (Kingsmore 2013, p. 2). The potential implications of the risks associated with false-positive results form an important part of the evaluation of appropriate disease targets for genetic screening programs.

Carrier Status For Autosomal Recessive Disease

Screening programs that aim to identify unaffected carriers of recessive disorders have been in place for several decades, with the initial programs designed to lower the birth incidence and thereby the population burden of the more common disorders such as beta-thalassemia in Cyprus and Tay-Sachs disease among Ashkenazi Jewish communities. As with prenatal screening, this adoption of an explicit goal of a lower birth incidence raises potentially contentious issues such as (i) the potential for disrespect toward affected individuals, (ii) the potential for social stigmatization of carriers, especially as marital partners, and (iii) the potential for the coercion by the government and/or the community of those who wish to decline participation.

As developing countries approach the demographic transition and infant mortality falls, genetic disease becomes more readily visible and at the same time more treatable. If treatment is expensive and needs to be lifelong to be effective, the improving survival of affected children can lead to the steady growth in the number of affected patients. If the cost of treatment is relatively high for the country’s economy, it may be impossible (i.e., unsustainable) for them to adopt a program of effective treatment (e.g., for betathalassaemia) without at the same time introducing a program of carrier testing with the clear purpose of reducing the birth incidence. While wealthier countries will usually avoid such explicit linking of the costbenefit drivers and consequences of genetic screening, masking it with talk of “informed reproductive decisions” (as if this were a goal rather than a condition of screening), such “political correctness” may be sidelined in countries where more is at stake.

When screening is seen as the only moral option, those who decline may be regarded as immoral. Among the more orthodox of the Ashkenazi Jewish population, Dor Yeshorim (Upright Generation) is seen as of broad societal benefit and, indeed, as an obligation of responsible reproduction for the prevention of Tay-Sachs disease and other autosomal recessive conditions common in this subpopulation (Leib et al. 2005).

There is significant variation in how such screening programs are made available: individual testing as opposed to couples-based testing, with the provision either of individual results or the combined status of the couple, and testing in schools as opposed to testing through community groups or cultural health services. Important considerations include the impact of knowing one’s carrier status on emotional well-being and self-esteem, in addition to the appropriateness of environments such as schools as a setting for such screening. Measures which support neutral information provision and encourage informed autonomous decision-making must be evaluated and examined empirically. Problems can arise when a screening program is targeted at a lower status ethnic group if there is any suspicion that carrier status is used to justify social (and therefore racial) discrimination. The screening for sickle cell disease (SCD) in USA in the 1970s attracted strong criticism because of such concerns aroused in the black (Afro-American) community.

One context in which the identification of carriers occurs as a secondary consequence of screening is newborn screening, especially for SCD and cystic fibrosis. Screening for SCD usually detects the HbS protein, so that all carriers are identified as well as patients (which the program is designed to detect). In CF screening, only a modest proportion of carriers is identified (those in whom the trypsin level is raised and who also carry a mutation detected in the initial CFTR mutation panel). Policies are highly variable regarding whether or how these results are reported. At least in UK and USA, health services are reluctant to hold information that is withheld from patients and so carrier status is usually reported to the child’s parents. This is ethically contentious as the implications of carrier status are often not communicated adequately or well understood by families. In addition, it is not always clear how information revealed in this manner is communicated to children once they are older, when such knowledge and its implications for reproductive decision-making are becoming more salient.

The most recent question to arise about genetic screening programs that identify carrier status concerns the advent of exome or whole genome sequencing, in the course of which the individual’s carrier status will be revealed for any or all disorders unless the analysts choose not to identify carriers or the clinicians decide not to reveal it to the patient (or parent). In effect, this becomes the question of whether carrier status counts as an important Incidental (or “secondary”) Finding that should be disclosed (vide supra).

Prenatal Genetic Screening

As with the identification of carrier status for autosomal recessive disease, prenatal genetic screening can be seen as either promoting autonomy in reproduction or as a socially coercive program, imposing unsolicited burdens on decision-making in pregnancy and amounting in effect to a program for reducing disability and disease in offspring. As such, the societal impact of comprehensive preconception screening is significant, particularly for those with disabilities. Reconciling the perspectives of affected individuals, families at risk of having an affected child, and society, with its idealized expectation of meeting the medical and social needs of all its members, is highly complex and challenging (Wert et al. 2012).

The complexity of the arguments and bioethical debate surrounding prenatal genetic screening has resulted in a large critical literature in this area, a full discussion of which is beyond the remit of this summary. Many arguments against prenatal genetic testing and screening center on the disability rights critique, which argues that testing for genetic disorders in future persons is disrespectful toward those affected by such conditions and morally objectionable. It is represented as, at best, frivolous and discriminatory, and at worst as tantamount to a coercive eugenics. In this context, prenatal screening is seen as a contributing factor to wider negative societal attitudes toward disability, decreasing the very diversity that could be productive in counteracting such attitudes.

Two molecular genetic technologies are having a substantial clinical impact on decisions about pregnancy. Preimplantation genetic diagnosis can be used to ensure that an IVF conception is not implanted into the woman if it is affected by a serious genetic disorder. This approach is likely to remain little used because it requires IVF, which is itself burdensome and expensive and not without risks. Likely to have a much greater impact on the general experience of pregnancy is noninvasive prenatal genetic testing (NIPT) of cell-free fetal DNA found in the maternal plasma. The more sequencing of free DNA from maternal plasma is achieved, the greater the scope of the questions that can be asked. Exclusion (or confirmation) of a fetal trisomy is a simple task achieved through NIPT, or the identification of a Rh-positive fetus in a Rh-negative mother, while complete sequencing of the fetal genome is much more demanding but can also be achieved. Many prenatal screening tests are likely to be superseded by NIPT so professionals need to appreciate the limitations of sequencing in this context. The principal objection to NIPT for prenatal screening is that it is so simple that patients may be less likely to think through the issues in advance of testing but they may also find it harder to decline testing if that is what they wish to do because the former “excuse” (concern about the risk of miscarriage from an invasive test) will soon evaporate and cease to supply a “reason.”

Newborn Screening By Whole Genome Sequencing (WGS)

Newborn screening by WGS is perhaps the most contentious topic raised by next-generation sequencing. It could never be enough for newborn screening to use only WGS as the commonest disorder being sought in most populations is congenital hypothyroidism, which does not usually have a specific genetic basis so that it would be missed by WGS however rapidly reported. If immunoassays for hypothyroidism are combined with WGS, however, there is the potential to diagnose many other genetic conditions and recognize many genetic predispositins, although conventional biochemical screening has at least two great advantages. These are that (i) the conventional method is more rapid and (ii) there is a functional element to the test, so that the difficulty of interpreting the phenotypic significance of genetic variants is greatly diminished.

There are at least three major classes of problems that can be anticipated in relation to newborn screening by whole genome sequencing as a population program. These are

(i) The generation of results of uncertain significance that requires (often costly and anxiety-provoking) further investigation and follow-up of the child.

(ii) The weakness of the assumption that genome sequencing will be a once-in-a-lifetime event so that it might as well begin early, allowing everyone to benefit from it for as long as possible. In fact, there are real costs of data storage and the maintenance of information systems compatibility, as well as potential problems relating to data protection and confidentiality (Chadwick et al. 2013); if most of the data remain unused for several decades it would seem much more appropriate to wait and analyze the genome as and when the information is needed. Over the next decade one can expect that costs of sequencing will fall, speed of analysis will increase, the interpretation of variants will improve enormously, and the scope of WGS will actually expand to include CpG methylation, chromatin configuration, etc. so that it would need to be repeated in any case to remain useful.

(iii) The generation of information that is predictive of disease, or at least indicating an increased risk of disease, in adult life with no health benefit being gained in advance, or of information of relevance to future reproduction but not the child’s health in childhood. Generating this information so early will either introduce (potentially poisonous) secrets into the family or take away the child’s right to an open future and the autonomy to make their own decisions about genetic testing.

These considerations lead to a modestly cautious approach to the use of genomic methods in newborn screening, acknowledging a role for targeted NGS in the diagnosis of specific disorders but not the use of unfocused, genome-wide approaches. A consensus on this topic has been reached by a broad-based group and endorsed by several international organizations active in genetic research and policy (Howard et al. 2015).

Evidencing Genetic Screening

This is an increasingly complex activity as genetic screening using whole genome methods represents a significant change in approach from phenotype-first to genotype-first disease identification. The majority of scientific evidence supporting gene-disease relationships derives from genetic testing in groups known to have or be at risk of a particular disease. In this context – of a genetic disorder in the patient being examined or a close relative – the finding of a possible pathogenic variant at a relevant locus is highly likely to be a true disease-causing variant. A similar finding in someone without a family history is much more challenging to interpret. The benefits to be gained by additional health screening or preventive measures in this setting are much less certain than when an individual has a strong family history and is identified as carrying their family’s known, disease-associated mutation.

Ensuring Equity Of Access And Effectiveness Across Populations

There are three distinct issues raised by considering equity of access to clinical genomic services: equity within countries, equity between countries, and equity of “ethnic representation” within research. The first two issues are not addressed as they are not specific to genomics but apply to health care in general. The specifically genomic issues arise because some communities have contributed much more to genomic research than others, so that the chance that a mutation relevant to disease will be recognized within that population is substantially greater.

Mutation panels have variable sensitivities in different ethnic groups, with an inevitable bias toward the recognition of previously reported mutations. This means that mutations are less likely to be found in those from less studied populations, so that those of European extraction will be better served in the case of autosomal recessive disease and diseases that date back many generations, while there will be much less bias in conditions that usually arise as new mutations. Reproductive isolates, such as can arise within communities that practice customary consanguinity, will only benefit from the new technologies if their recessive disorders have already been reported or if intrinsically unbiased technologies are used (e.g., exome or whole genome sequencing) but not if diagnostic panels of previously reported mutations are used.

Less sophisticated methods of screening such as biochemical approaches using tandem mass spectrometry (TMS) are not associated with the same problems and offer a more equitable method of screening diverse populations. The genomic approach demands an additional step of analysis – bioinformatic – for each individual screened, while methods closer to the phenotype of relevance (biochemical rather than genomic) require less analysis specific to each individual screened and are therefore more equitable when resources are restricted. While public health approaches entail significant practical and ethical challenges, restricted access to these genetic technologies denies them to those at greatest need of population-level health improvement (McClellan et al. 2013).

Role Of The Government And Public Health Bodies

 Ultimately, decisions about which diseases to screen for are political decisions. These decisions must balance the evidence basis for the cost-effectiveness of identifying disease, and disease risk, in a given population and the consequences of this for the wider health system, and for the healthcare consumers. Governments must also support sectors, such as genomics and biotechnology, which provide potentially significant economic benefits. While the process of performing a particular test may be inexpensive, use on a population screening level needs support from education programs, pre and post-test counseling, confirmatory and cascade testing, medical interventions, and further follow-up – all of which are costly and resource intensive. It is only through a rigorous, objective, evidence-based review process, rather than by technological capability, advocacy, and individual opinion, that decisions about genetic screening should be made. Establishing professional bodies to oversee this process such as the National Screening Committee (UK) or National Testing Center (New Zealand) provides an essential safeguard against abuse and allows programs to be locally tailored according to the needs of the population. Although screening may be provided by government-supported public health systems, it is important that this remains distinct from mandatory participation – individuals are “invited” to participate, based on the evidence that participation provides net benefit, rather than harm. Making this distinction to participants can be particularly challenging, particularly where screening is difficult to distinguish from standard medical practice or care, for example, the inclusion of trisomy 21 screening in antenatal care during pregnancy.

While the scope of what we are technologically capable of screening for continues to increase, our knowledge of how genetic susceptibility testing would benefit health through behavior change remains unclear. Genetic screening for disease loci may be of benefit when those identified as positive must merely comply with programs of treatment or enhanced surveillance. However, when changes to behavior and habits are required to gain health benefit, susceptibility testing is thought to have a more modest impact on health related behaviors. As such, the issue becomes an examination of the measures it is legitimate for governments to employ to effect behavior change in citizens (Nuffield Council on Bioethics 2010).


Despite attempts to define screening criteria, the choice as to which set of criteria to use remains intrinsically subjective. There is a complex interplay between the technological, political, economic, public health, ethical, and legal factors influencing which conditions are currently screened for, and the reality of financially feasible high-throughput genomic technologies further complicates the matter of which genes or diseases are appropriate targets for screening on a population level. Patient and industry advocacy groups can similarly distract from the need for evidence to support new screening targets. Can a process be developed that will guide the process of making decisions about the extension of genetic screening in a rationally defensible manner?

The potential health benefits of screening for susceptibility genes must not be exaggerated. There remains a long-standing lag between the ability to screen for and recognize diseases and the ability to make evidence-based interventions that will helpfully modify the course of the disease. While screening for such mutations may be appropriate for the commercial direct-to-consumer test, or indeed the physician-mediated opportunistic screening currently advocated by the ACMG (Green et al. 2013), such approaches are not currently feasible and would not be desirable on a population-level health service.

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