Sociohumanitarian issues of preconception genetic screening programs

Vetrov Vladimir Andreevich Editor, Center for Scientific and Information Research on Science, Education and Technology, INION RAS, Moscow 117218, Russia, Moscow region, Moscow, Nakhimovsky ave., 51/21 vetrov21v10@gmail.com

Introduction

Preconceptional genetic carrier testing (PGTN) or, as it is often referred to in English–language literature, Extended carrier screening (ECS — Expanded Carrier Screening) is a genetic study offered to the general population or couples who have no known risk of recessive and X-linked genetic diseases and who are preparing to become parents (therefore, the test or screening is often called "reproductive"). The test can simultaneously detect the carrier of several autosomal recessive diseases. Couples with a positive carrier test have various options for realizing their reproductive autonomy. So, they may decide to put up with a 25% risk of having a child with the disease and do nothing, or try to minimize the chance of developing the disease. Risk avoidance options range from non-medical options, such as not having children, custody, or even changing partners, to the use of assisted reproductive technologies, such as in vitro fertilization (IVF) and preimplantation diagnosis, prenatal diagnosis (if pre-conception testing was already performed during pregnancy) or sperm/egg donation.

According to research, today one of 1,300 known recessive genetic diseases affects at least three children for every thousand. Diseases with recessive disease may be relatively rare if they are considered separately, but if they are considered as a group, they become epidemiologically significant ^[1].

The reproductive risk of recessive diseases is particularly high in incestuous couples and geographically isolated populations. Thus, persons of Ashkenazi Jewish origin usually undergo a carrier test in adolescence or before starting a personal relationship. It is known that the Ashkenazi Jewish population is at high risk of developing certain genetic diseases due to the high incidence of certain recessive diseases that are usually less common in the general population, such as Gaucher type 1 disease and Tay-Sachs disease. Targeted ethnic origin testing strategies have been effectively applied in several geographical regions suffering from specific genetic diseases (for example, cystic fibrosis in the USA, Australia and Italy, beta-thalassemia in Cyprus, Sardinia, Israel and Turkey), dramatically reducing the incidence of the disease in newborns^[2]. As a result of genetic testing before conception and subsequent informed family planning, a significant decrease in the incidence (from 47% to 90%) of serious monogenic diseases, such as cystic fibrosis and ?-thalassemia, was registered ^[3].

Previously, genetic testing before conception was offered mainly to couples with a positive family history of a genetic disease or to specific communities and regions with a high prevalence of these diseases, as in the examples described above. However, recently the technology has become more reliable and accessible, which allows considering the possibility of mass screening for carrier among the population. Individually, these diseases are rare, but together they lead to a significant proportion of infant mortality (about 20%) and hospitalizations (about 18%) ^[4]. In addition, the use of pan-ethnic strategies in testing makes it possible to overcome the known limitations and inaccuracies associated with self-reporting about ethnicity.

Despite the general consensus on the theoretical and practical usefulness and value of PGTN in healthcare, large-scale clinical implementation at the program level can pose serious problems for healthcare professionals and all stakeholders. The introduction of advanced carrier screenings requires an expert assessment of specific, but interrelated and equally important aspects: technical, ethical, legal, social.

At the same time, the problems of PGTN (especially ethical) in one way or another, they are connected with uncertainty, which in turn has 2 sources: technological, limiting the accuracy of determining the phenotypic manifestation of some genetic variants, which will be overcome one way or another (looking optimistically at the development of genetics) and fundamentally conceptual. The author believes that a satisfactory consensus on the problems of the "second category" within the framework of expanded programs of preconceptional screening can be achieved only with the participation of humanities scientists, since even developed analytical tools and extensive empirical research may be insufficient in making decisions on fundamental issues, socio-humanitarian disciplines have a significant advantage here.

In this paper, three interrelated problem areas are identified, which, according to the author, are associated with fundamental uncertainty and cannot be solved without deep socio-humanitarian reflection, namely:

1.                     Determination of the severity of the disease

2. Routine and eugenic risks

3. Goal setting

Each of the issues is assigned a separate paragraph, which also examines the impact on the implementation of PGTN programs. The study of the identified problems (and their impact) can help overcome current obstacles or controversial issues in the implementation of preconceptional genetic screening strategies, moreover, some of the conclusions of their such consideration may be useful for other types of genetic testing and healthcare in general.

Determination of the severity of the disease

With the emergence of technical possibilities for screening an increasing number of genetic variants, one of the most important points is the choice of genetic variants included in the screening panel, since even if there is a desire to "check everything" (the disputability of such an aspiration will be written below), the state program will inevitably meet with economic restrictions. A key topic in the development of large-scale gene carrier screening programs is the concept of severity or severity of a possible disease (we are talking primarily about incurable and chronic diseases or those with a limited period of available intervention). For example, among the criteria used in the selection of genes in the Australian McKenzie Mission project, there was an indication that the condition should be included in the extended screening only if a typical couple "takes steps to avoid having a child with such a disease" ^[5].

Several professional societies have published recommendations on the selection of conditions in extended carrier screening panels ^[6]. According to these recommendations, clear criteria should be established for the formation of the panel, instead of including as many diseases as possible. The tested genes must have a strictly defined relationship with the phenotype. Moreover, the condition should cause cognitive or physical impairments, have a detrimental effect on the quality of life, require medical or surgical intervention, or have an early onset ^[7]. The European Society of Human Genetics also states "that the natural course of the disease being screened should be adequately understood, and that an acceptable and reliable test with known sensitivity, specificity and prognostic value should be available" ^[8].

One of the severity classification algorithms was proposed and evaluated in a study conducted among 192 medical professionals. In this algorithm, the characteristics of the disease were distributed by severity on 4 levels ^[9]:

1)Reduced life expectancy (death in infancy, childhood, adolescence), intellectual disability

2) Reduced life expectancy (youth), mobility disorders, dysfunction of internal organs

3) Sensory dysfunction (vision, hearing, touch, etc., including pain), immune deficiency, cancer, mental illness, dysmorphia

4) Infertility or limited fertility

Using the characteristics of the disease, the conditions according to this algorithm can be classified as mild, moderate, severe and very severe:

Very severe (profound) conditions have more than 1 level 1 characteristic. Severe or severe conditions have at least 1 level 1 characteristic or several level 2 or 3 characteristics. Moderate conditions are diseases that have at least 1 level 3 characteristic, but do not have other level 1 or 3 characteristics. 2. Mild diseases are diseases without any level 1, 2 or 3 characteristics.

The experts suggested that with extended carrier screening, priority should be given to screening for "severe" and "very severe" conditions. "Moderate" diseases can also be included in screening if the results can enable early intervention ^[6].

However, severity as a criterion is controversial in practical application, ethically ambiguous, and, most likely, there are different and irreconcilable opinions about when and to what extent the condition is serious/severe.

A quantitative assessment of the characteristics of diseases (like the one above) only partially answers the question of whether the condition is severe enough to be included in the screening panel. Indeed, this approach makes it possible to clarify the criteria, which provides greater consistency and objectivity in interpreting the requirements for the severity of the disease in the selection of genes for testing. Although such tools are undoubtedly valuable, the example of a mutation of the CFTR gene responsible for cystic fibrosis (in which disorders of the function of the endocrine glands are observed, manifested by severe disorders of the functions of the respiratory organs, gastrointestinal tract and other organs and systems), demonstrates the complexity of classifying a condition in which different expressivity can be observed (that is, severity and the very presence of symptoms, even if there is the same genotype in different people, can differ significantly). There is a broad consensus that the classical form of cystic fibrosis requires the inclusion of the CFTR gene in the reproductive screening of carriers. However, it is less clear how to treat the lighter variants of CFTR ^[10]. The question arises as to which options should be identified in the context of carrier screening.

The next question is: can the severity of the condition when assessing the feasibility of implementation in the screening panel depend on individual perception, or is the severity something that relates to a medical condition regardless of the patient's attitude? The severity of infertility for an individual depends on the presence or absence of a desire to have children; if a person has no desire to have biological children or offspring at all, it is unlikely that he will perceive the state of infertility as severe, and vice versa. Severity can be assessed in different ways depending on the patient's suffering (which is also strictly individual), medical prognosis, disability, and other things. Certainly, perception turns out to be significant in determining the severity of the disease, at least partially. However, when and to what extent? How do ethical and existential attitudes, coupled with society, affect the severity of an individual's attitude to his condition (or his child)? How then should the severity be assessed, what additional criteria should be taken into account? These issues require, firstly, reflection on the relationship between subjective well-being, the views of society and the objective characteristics of the disease, and secondly, methodological development.

The objective (symptomatic) severity of the disease is also not always easy to determine: diseases, as a rule, manifest themselves differently in people (and, as indicated, people react differently to them, which further complicates the assessment, since healthcare is basically a social phenomenon). At the same time, the severity of the disease can change over time, even in patients with chronic diseases. A high level of phenotypic variability and different expressiveness lead to the fact that the results of genetic susceptibility tests leave patients with significant uncertainty about the severity as well as the onset of the disease, which is undesirable in a large-scale program.

International guidelines on genetic testing require that medical supervision and genetic counseling be provided during genetic testing. They point out that the form and scope of genetic counseling "should be determined depending on the consequences of the test results"^[1] and "should be proportional and consistent with the characteristics of the test, its limitations, the potential for harm and the significance of the test results for individuals and their relatives" ^[11].

Reproductive testing can carry potential harms such as health risks (e.g. unnecessary surveillance), psychological risks (anxiety) and social risks (financial costs, discrimination). Therefore, in the ethical evaluation of genetic testing and screening services, traditionally the main criterion is a favorable balance between risks and benefits, i.e. between the principles of benevolence and non-harm ^[12].

The availability of therapeutic interventions is the main advantage and justification for genetic testing or screening. However, in the last few decades, when medicine partially shifted the focus from treatment to prevention, the concept of treatment began to include other "meaningful options for action" ^[13], which were added primarily to include decision-making on reproductive issues. Thus, the ACCE system (an analytical process named from 4 criteria: analytical validity, clinical validity, clinical usefulness and ELSI aspects, consisting of 44 target questions^[2]) presents preventive options and actions as possible advantages of screening: it requires that there is an "effective remedy, acceptable action or other measurable advantage". In the context of genome testing with a wide variety of diseases that are being tested for, the possibility of action has become a more appropriate concept than the possibility of treatment, although there are some collisions when questions arise – should patients know about the possibilities of this action (as well as about the potential disease itself) and how to assess the volume genetic counseling regarding the results of carrying such a mutation. Decisions such as choosing a complex and expensive IVF pathway with preimplantation genetic testing or, if pregnancy has already occurred, prenatal diagnosis with the possibility of termination of pregnancy, can be especially difficult if the choice is based on the results of a genetic test with uncertain consequences.

An important point when reporting screening results is whether and how the information provided will be useful for participants. One of the main ethical compromises when making decisions about informing is whether it will be worse for the program participants if screening does not reveal those who have a high probability of having a child with a certain disease, or whether it will be more harmful for people to get information about an option that is very complex and uncertain. Such information can lead to the fact that people with an increased probability of having a child with a certain combination of options may take unnecessary steps. Such information can be more burdensome than useful for the family.

All the described uncertainties can create problems for the provision of information before and after preconceptional testing and for the processes of voluntary informed consent. Alternative strategies for reporting options may be required, which may limit it to combinations of options that are associated with severe clinical manifestations (which, however, does not eliminate the need for a thorough study of the concept of "severity").

Routine and eugenic concerns

Since the increased autonomy of some may influence the choice of others, it is advisable to pay attention to how the movement towards the normalization of the use of PGTN and, in particular, the introduction of expanded pre-conception screening programs may lead to the fact that it will be more difficult for couples to refuse these services in the future ^[14].

By offering an opportunity for additional reproductive control, the growing appeal to pre-conception genetic testing and especially the introduction of screening programs can potentially create a social expectation to take advantage of this control, which in some cases (a number of which were discussed above) can become an additional source of concern.

If screening begins to be perceived as routine, people may be less critical about whether it is right for them, or consider the value of the results for their reproductive choices. A well-known example is ultrasound examination and prenatal diagnostics, which have become commonplace in many countries. Most women undergo these procedures, and studies show that most consider such tests to be a "responsible choice" that also "protects the health" of their child, although abortion is the only alternative to having a child ^[15]. This makes researchers wonder to what extent people have independent choice in such situations. The introduction of screening programs can lead to similar criticism. It should be noted that healthcare is not necessarily the driving force behind the shift in regulatory expectations. Couples and their social environment may well be significant factors in this development, which implies that any adjustment efforts should take into account medical professionals and patients, as well as their partners. The features of the PGTN and the expanded screening panel, as mentioned above, make risk assessment and determination of the benefit/harm ratio problematic for both couples and medical professionals advising them.

The solution in this situation may be decision-making support prior to testing, such as educational videos and decision-making manuals that will help couples consider the consequences of positive carrier results and their reproduction options.

The problems associated with routine are discrimination and stigmatization, both in relation to those who will have a positive carrier result, and in relation to children with genetic diseases. The researchers emphasize the risk of additional social pressure on carriers of the recessive trait in the situation of full implementation of preconceptional screening programs ^[16]. The broader ethical debate concerns the so-called expressivist argument. According to him, the preconceptional tools that can be used to avoid the birth of children with certain signs express a negative attitude towards people with these signs. The expressivist argument and concerns about discrimination are obviously more relevant for tests with panel designs that include signs of diseases that allow a person to live a relatively "normal" life. As mentioned above, there are very serious diseases with an early onset that are incompatible with life in general or severely restrict it / cause excessive suffering, and in such cases this argument does not cause moral contradiction. However, if the screening panels include signs of diseases associated with incomplete penetrance, late onset and a slight deterioration in the quality of life, then such programs will definitely face an ethical objection.

An even more serious problem, "raised to the absolute", associated with the PGTN programs, is the possible interpretation of it as eugenic in intent or results. In a broad sense, eugenics describes a set of methods (political, social and medical) aimed at the development of certain characteristics or their exclusion within the species by manipulating heredity. Genetic screening for reproductive purposes, often carried out in order to avoid the birth of a child with certain genetic diseases, has some common features with eugenics, since it can affect which people will be born, and requires from the institutes of health (in the case of a state screening program) a certain idea of the level of health that requires certain reproductive decisions.  And if, again, actions regarding severe and very severe diseases mostly avoid eugenic accusations, the debatable question of the intrinsic value of life and neo-eugenics in modern society remains relevant.

Although from a scientific point of view, preconceptional screening programs are unlikely to significantly change the genetic composition of the population, there is concern that even the supposed possibility of such a change may affect social norms and attitudes (both positive and negative) ^[17]. Although genetic variants manifest phenotypically, how these changes will affect the quality of life depends on the socio-ecological context and on cultural and social perceptions of disability.

The sociocultural context shaping reproductive decision-making reflects epistemic norms regarding the understanding of disability ^[18]. Some of the important objections to screening for genetic diseases before conception are partly based on a social, rather than biomedical, model of disability ^[19]. If the biomedical model defines disability as a deviation from a certain norm, then the social model of disability recognizes that the violation includes a physical and/or intellectual anomaly, which means that the degree of disability depends (to a certain extent) on the social and environmental response to this violation. Socio-environmental factors may include attitudes, such as discrimination or acceptance, as well as practical elements, such as wheelchair ramps and assistance measures for hearing-impaired and deaf people in public institutions. Government screening initiatives can actually reduce the level of acceptance and support of people with disabilities by society, especially if they lead to fewer people living with certain types of disabilities (and, consequently, the need for specific socio-environmental interventions will decrease).

If any disease is included in the panel, it intuitively begins to be perceived by future parents as requiring some kind of intervention. The point of view of people living with disabilities is rarely available to potential parents. This reflects the dominance of the medical point of view, which can be considered as a form of epistemological injustice, since the life experience of people with various diseases is usually marginalized and less noticeable within the framework of the basic social understanding of such diseases ^[20].

Although the concept of a decent standard of living is largely shaped by the social context, the design of a screening program can also have an impact to a certain extent. The choice of diseases for screening within the framework of the PGTN, as well as the ways of proposing and evaluating options for further intervention normalize or strengthen certain views and values. All this is part of the normative social context that influences how individual couples will evaluate their reproductive capabilities and make decisions.

A global consequence of the widely proposed pre-conception screening program may be a decrease over time in the number of people born with diseases for which screening is carried out. The probability of such an outcome is based on the experience of prenatal screening for genetic diseases ^[21], as well as on existing carrier screening initiatives ^[22]. If there are fewer people living with disabilities and differences, then society may become less tolerant, sympathetic and supportive of people living with genetic diseases. In other words, the generally accepted understanding of what makes a person "the best" may narrow over time. This normative drift is likely to affect the reproductive decisions that people make. However, it can also have a negative impact on the well-being of people with disabilities in society.

Goal setting of screening programs

One of the most important issues for large-scale preconceptional screening initiatives is how their goals are described. The two main directions for formulating the goals of such programs are, firstly, the result for individuals and their families, that is, first of all, the impact on reproductive autonomy; secondly, the result for populations, such as a reduction in the incidence of certain genetic diseases.

The goal aimed at reducing the population morbidity of children with severe genetic diseases may not be suitable for reproductive screening ^[23]. This position is based on concerns related to the routine practice. In addition, such a goal can be interpreted as implying that couples who have received a result with an increased probability of illness are obliged to take measures to avoid the birth of a child susceptible to the disease.  Also, the goal of reducing the incidence of certain genetic diseases among the population may express an unfavorable judgment about the value of the lives of people who are currently living with such a disease or may be born in the future. Therefore, in the case of preconceptional screening, it is more ethically acceptable to increase and support the reproductive autonomy of couples by providing more extensive information about potential diseases and risks associated with them, allowing them to make a choice in accordance with their values ^[8].

In this regard, it is advisable to support the reflections of participants in a potential program about their values and testing goals in order to help them decide whether this screening will be useful and important for them ^[24]. In addition, the results of any genetic test can be complex and uncertain, so the test results should be presented in such a way that they are both instrumentally and axiologically useful. 

Reporting options that are not clinically relevant or create uncertainty for people who have been screened may prove problematic in the context of population-based preconceptional genetic testing. As screening becomes more and more accessible, consulting support of the results will increasingly be, at least partially, carried out by medical professionals who do not have special training in genetics, and despite the fact that most medical professionals have a certain degree of genomic competence, there is constant concern about their ability to transmit complex genomic information ^[25].

To optimize the usefulness of the results, participants will need a basic understanding of key concepts, as well as the consequences of carrier detection. It is also important to ensure that participation in screening is not interpreted as a guarantee that the couple will have a healthy child.

The development of PGTN screening panels requires an assessment of the potential impact of exposure to this condition on a sick person and his family . General population carrier screening programs will definitely not be focused on providing information about mild genetic conditions (whatever criteria they are determined by). The criterion of the severity of the disease itself will be constantly problematized in each individual case of the introduction of a screening program and require clarification from the initiators of the program, taking into account the social context

At the same time, the scientific understanding of genetic variants and their impact on health is constantly evolving, so the revision of gene lists is also an important component of expanded genetic screening programs. A condition that was not previously included in the list may require inclusion in the screening panel if it becomes more understandable. Similarly, it is possible that increased knowledge about a gene or condition may justify its exclusion from the preconceptional screening program. Since genes are interpreted and reclassified in a new way, the question of whether and how to convey this information to previous participants of the program is complex and requires comprehensive consideration and planning ^[26].

Conclusion

One way or another, determining the conditions that should be included in the screening panel of a large-scale program is one of the most debatable problems. The aspects of screening implementation considered in this paper, which are variously related to the formation of the PGTN panel (severity determination, goal setting, routine/eugenization), are important to take into account at the stage of gene selection for extended carrier screening. These factors require a careful approach to the development of screening panels, taking into account the probabilistic value (and, accordingly, harm) of the information obtained as a result of screening, and the possibility of implementation in large and diverse populations.

Some decisions about which genes to include in the panels are more difficult, since the clinical picture of the disease can be extremely unstable. Interpretation of variants can also be problematic, especially if mutations are rare, and other additional factors such as epigenetic effects, environmental effects, and modifier genes may also be present. Variable expressiveness and incomplete penetrance generates uncertainty and is one of the elements that can make it difficult to determine the consequences of carrier screening results.

 Since screening can be stigmatizing for people living with genetic diseases or even carriers for whom screening is carried out, it is considered the most ethically justified to screen only for genes associated with severe childhood diseases (which is reflected in existing practices). However, since the perception of the severity and severity of the disease is not purely objective, any screening program for carrier should carefully weigh the various ways of manifestation of the disease, as well as the consequences of this condition for a person and his family.

Given the extremely complex and uncertain nature of some genetic variants, it is necessary to carefully consider the balance between providing potentially burdensome or harmful information and providing valuable information to justify reproductive decisions.

One option to alleviate some of the ethical concerns for extended screening may be to adopt smaller gene panels and exclude options when uncertainties like the three considered arise. This will require a shift from the point of view that screening is designed or interpreted as an opportunity to "find everything" to the point of view that screening is designed to identify a well-compiled and reliable list of conditions that meet the requirements, including resource savings in presenting results, ease of obtaining results (including by non-specialists) and the value of information for steam. A conservative approach that can be implemented on a population-wide scale, and which reports only those options (or combinations of options) that will be valuable for making reproductive decisions or interventions at the very beginning of life, should be the default option, and any deviations from it should be clearly justified.

Nevertheless, even with the adoption of a strategy to minimize all risks associated with screening and radically reduce the screened conditions, fundamental problems will remain in each of the considered aspects of the implementation of large-scale PHTN programs that require socio-humanitarian and, in particular, philosophical reflection. Clarifying the concept of the severity of the disease, determining the most suitable goals for healthcare, assessing the long–term risks of eugenization of society and stigmatization of carriers of genetic mutations - all these tasks cannot be solved only by improving diagnostic tools, they require epistemological, existential, sociological and general humanitarian study. Only by embedding humanitarians in the examination of preconceptional genetic screening programs is a systematic and broadest resolution of the above problems achievable.

^[1] See Council of Europe: Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Genetic Testing for Health Purposes. 2008

^[2] See more details: https://www.cdc.gov/genomics/gtesting/acce/index.htm

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