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What ethical and legal principles should guide the genotyping of children as part of a personalised screening programme for common cancer?
  1. Alison Elizabeth Hall1,
  2. Susmita Chowdhury1,
  3. Nora Pashayan2,
  4. Nina Hallowell1,
  5. Paul Pharoah3,4,
  6. Hilary Burton1
  1. 1PHG Foundation (Foundation for Genomics and Population Health), Cambridge, UK
  2. 2UCL Department of Applied Health Research, University College London, London, UK
  3. 3Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK
  4. 4Department of Oncology, University of Cambridge, Cambridge, UK
  1. Correspondence to Alison Elizabeth Hall, PHG Foundation (Foundation for Genomics and Population Health), Cambridge CB1 8RN, UK; alison.hall{at}phgfoundation.org

Abstract

Increased knowledge of the gene–disease associations contributing to common cancer development raises the prospect of population stratification by genotype and other risk factors. Individual risk assessments could be used to target interventions such as screening, treatment and health education. Genotyping neonates, infants or young children as part of a systematic programme would improve coverage and uptake, and facilitate a screening package that maximises potential benefits and minimises harms including overdiagnosis. This paper explores the potential justifications and risks of genotyping children for genetic variants associated with common cancer development within a personalised screening programme. It identifies the ethical and legal principles that might guide population genotyping where the predictive value of the testing is modest and associated risks might arise in the future, and considers the standards required by population screening programme validity measures (such as the Wilson and Jungner criteria including cost-effectiveness and equitable access). These are distinguished from the normative principles underpinning predictive genetic testing of children for adult-onset diseases—namely, to make best-interests judgements and to preserve autonomy. While the case for population-based genotyping of neonates or young children has not yet been made, the justifications for this approach are likely to become increasingly compelling. A modified evaluative and normative framework should be developed, capturing elements from individualistic and population-based approaches. This should emphasise proper communication and genuine parental consent or informed choice, while recognising the challenges associated with making unsolicited approaches to an asymptomatic group. Such a framework would be strengthened by complementary empirical research.

  • Public Health Ethics
  • Autonomy
  • Newborns and Minors
  • Genetic Screening/Testing
  • Genethics
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Introduction

Over the past decade, multiple common genetic variants (CGVs) associated with susceptibility to late-onset diseases have been identified, mainly through large-scale, genome-wide association studies. Individual CGVs typically confer small increases in disease risk and have no clinical utility. However, in combination, CGVs can confer a sufficiently wide distribution of risks in the population to be clinically relevant. In particular, a combination of genotype (multiple CGVs) and other lifestyle risk factors could be used to preferentially target interventions such as cancer screening, at people at greatest risk. Such risk stratification could form the basis of ‘personalised’ screening, particularly for breast, prostate and ovarian cancers which occur commonly in the population.

Population-wide personalised screening through the genotyping of blood or saliva samples typically generates concerns among clinicians and policy-makers because the clinical utilityi of screening based on genotyping CGVs in different risk groups has yet to be established.1 However, risk-prediction modeling, capturing the impact of genotyping multiple variants, now offers a mechanism for exploring these effects. Modelling has been developed through the Collaborative Oncological Gene–environment Study (COGS), a large-scale multicentre initiative combining the systematic genotyping of germline susceptibility alleles for breast, prostate and ovarian cancer, the development of risk prediction models and evaluation of concomitant ethical, legal, social and organisational issues.2 This type of modelling allows calculation of composite genetic risks, and by integrating cumulative risk estimations from environmental exposure or lifestyle,3 screening is targeted more effectively. Recent pilot studies show the feasibility of targeting women attending existing mammography screening programmes to offer risk-reduction strategies and greater screening intensity to a subset of women,4 suggesting that risk-stratified screening based on genotype might also be feasible and might mitigate concerns about overdiagnosis.5

This poses the question of when genetic testing for risk assessment should take place. The offer of such a test during childhood, possibly as part of a wider risk assessment package for a range of adult disorders, was raised by experts attending a COGS international workshop and this paper examines the pertinent issues that might arise.

At present, debates about predictive genetic testing of children for adult-onset conditions have customarily focused upon relatively rare monogenic conditions (such as Huntington's disease and some hereditary cancers). Typically, these mutations are strongly penetrant, meaning that they are generally a good predictor of disease in later life and that positive carrier status has implications for other family members. Given this context, there has been prioritisation of the need to promote children's best interests and to safeguard their future autonomous decision-making, and childhood testing has been discouraged in the absence of clear clinical benefits.6–8 In contrast, most genetic variants and gene–disease associations that might be used in stratified or personalised screening are likely to be weakly penetrant, less proximate in time than those linked to monogenic diseases and poorly predictive of disease development, having minimal implications for other family members.

This paper explores the justifications for genotyping during childhood as part of a personalised screening programme, in the context of the ethical and legal principles that guide current professional practice for the genetic testing of children. It makes the case for developing an alternative normative framework which should apply to population-based genotyping of children and young people. In all the arguments that follow, it will be assumed that in order to safeguard against the possibility of third parties such as insurers, schools or employers discriminating against, or stigmatising, those who have been tested as children (or indeed as adults), data need to be processed, stored and transferred in ways that maximise participant confidentiality and privacy.

Risk-stratifying children for population screening: potential utility, benefit and harm

A prerequisite for implementing personalised screening in early adulthood would be population genotyping at some point during childhood or late teenage years. Leaving genotyping as late as possible might maximise the capacity of individuals to make competent decisions. However, integrating genotyping for common cancer risk assessment within the existing infrastructure for screening neonates, children and young persons, such as neonatal blood spot screening or neonatal vaccination in infancy, might be logistically and organisationally compelling if it offered increased coverage and uptake. A public health focus might support such a utilitarian approach because even where they are not compulsory, newborn screening programmes typically provide almost universal rates of uptake, although the consent process may not always be optimal.9 Moreover, the burgeoning scope of newborn screening in some jurisdictions also suggests that the modest clinical utility associated with some genetic variants, may not be a bar to introducing childhood genotyping as part of a systematic programme of population screening.10

The second benefit of childhood testing concerns the lengthy latent period between genotyping and disease occurrence, which might provide increased opportunities for primary preventative strategies such as lifestyle modification through diet or exercise. Health professionals could use test results to minimise exposure to known risk factors for common cancers such as breast or prostate cancer through appropriate lifestyle changes, chemoprevention or generalised health education about the promotion of healthy exercise, diet and avoidance of drug, smoking11 ,12 or alcohol addiction. Additional utility might result if genetic susceptibility information was integrated into pharmacogenomics programmes to direct drug treatments throughout life.13 Indeed, emerging evidence from modelling suggests that prospective participants infer that genetic testing would enable improvements in lifestyle mitigating their existing health risks and that this is a powerful predictor of test uptake.14

However, the existence of a latent period between testing and symptoms arising also provides an opportunity for intervening events to alter risk in a negative way, which some argue undermines the clinical utility of childhood testing.15 Concerns about lack of clinical utility are strengthened by evidence suggesting that behavioural change may be difficult to facilitate in both adults and children, and that communicating genetic risk information may result in a parental preference for medication rather than behavioural change, particularly in inherited conditions that are strongly penetrant such as familial hypercholesterolaemia.16 Particular care is needed when approaching an asymptomatic group rather than when genetic testing is prompted by a known family history of disease or other known risk factor, especially if an adverse result relates to an individual with no medical history.3 ,17

Despite these challenges, genotyping might be viewed positively by some parents anxious to determine their child's optimal environment. For example, Tercyak et al11 sampled members of a health management organisation to determine their willingness to have their children tested for 15 polymorphisms associated with increased risk for eight health conditions including colon, skin and lung cancers. Participants were given a number of alternative scenarios for testing. Those who held more favourable attitudes to testing their children tended to be considering testing themselves and to give more prominence to the potential benefits than the harms of testing. Those supportive of testing expected that they would respond positively to evidence of reduced risks. In another review assessing attitudes of social networkers to direct-to-consumer provision, participants expressed high rates of interest and of the 64% who considered using personal genome testing, 54% would use it to gain knowledge about disease in their children.18 However, hypothetical scenario-based research can be a poor predictor of actual behaviour, and the research did not record the personal characteristics of the research participants, although if these studies are representative of the direct-to-consumer genetic profiling market, those who embrace such testing are likely to be highly educated, white and scientifically literate.19 Such differential use within a personalised screening programme could create inequalities if it were ultimately shown that genome-based tests bring health benefits.

Some of the inherent uncertainties around parental attitudes could be resolved through enrolling teenagers to attend primary or secondary care providers for personalised genotyping: this might also mitigate concerns about maximising individual best interests and autonomy because these older children may be competent to consent to testing. However, this approach would be costly, and coverage and capture rates might be lower than by genotyping infants or young children. Providing genotyping as an adjunct to scheduled appointments for vaccination (human papillomavirus or tuberculosis) or contraceptive advice in the early teenage years might also result in (sexually active) young women being preferentially targeted.

The potential harms associated with population-based genetic susceptibility testing using multiple low penetrant genetic variants are difficult to assess, and given the recent development of these technologies, empirical evidence is sparse.20 However, possible harms can be hypothesised. First, genetic testing may result in direct or indirect psychological harm to children by generating increased anxiety about developing disease, fatalism or perceived lack of control.21–23 Healthcare professionals involved in the screening process could mitigate this by providing reassurance that positive results are weakly predictive and are more influential in determining the timing and nature of screening and possibly behavioural interventions than the onset of disease. However, even in the absence of positive test results, anxieties might still arise as a consequence of wider familial discussions about disease susceptibility.23

Second, genetic variant testing in children might prompt parental/carer anxiety24 or dysfunctional behaviour (such as overly protective behaviour).25 It is unclear whether, and to what extent, learning about polygenic susceptibility to multiple conditions might influence parenting practices26 ,27 and/or promote reliance on genetic variant information to the detriment of other evidence. Psychosocial research suggests that some parents expect to alter their behaviour in response to predictive genetic testing28 despite having reservations about its veracity.29 Indeed, research on cascade screening for hypercholesterolaemia suggests that knowledge of a child's predictive genetic information prompts changes in parenting behaviour.16 However, the lack of a causal relationship and evidence of benefit between genetic testing and parental lifestyle decision-making, suggests that these claims may be unwarranted, given that, once they are adult, individuals may reject behaviours that have been imposed upon them as children. Certainly in other settings, personalised genetic risk information might result in less behaviour change than predicted and observed changes may be transient, modest and strongly influenced by the context for risk communication.19 ,22

Further empirical research is needed to clarify the impact of providing genetic information which is weakly predictive of future ill health. Relevant evidence might eventually be generated from randomised controlled trials of interventions based on genotyping, coupled with long-term follow-up of large cohorts.

Finally, opinion is also divided as to whether personalised screening could exacerbate the medicalisation of some behavioural traits, (ie, the tendency for ‘normal’ human problems and conditions to fall increasingly under medical authority), such as the use of genotyping to predict future sporting aptitude and ability.30–32

Current legal, ethical and societal context for childhood genetic testing

How might population-based genotyping be interpreted in the context of current professional guidance on predictive genetic testing? There is considerable variation in the rights afforded to children or minors (ie, those younger than 18) across Europe, arising from cultural and religious beliefs, and existing legal and ethical frameworks. Despite these differences, which are reflected in variations in the medical and legal age of majority33 and some aspects of professional practice,34–36 health professionals can generally react flexibly to individual cases. Since discussions about ethical principles and derivative professional guidance6 tend to focus on monogenic diseases,28 this raises the question as to whether derogation from the general ethical principles that have been developed for childhood genetic testing in monogenic diseases could be justified within a publicly funded screening programme for common diseases.3

The dominant ethical principle underlying many of the guidelines questions whether predictive genetic testing is in the ‘best interests’ of the child. This ethical principle has been given judicial weight in multiple jurisdictions and settings, including healthcare and adoption law. Despite differences between countries as to how narrowly or broadly ‘best interests’ are defined and some examples of legal precedent leading to subtle differences in emphasis, there tends to be a relatively consistent reliance across Europe upon maximising a child's best interests in legal judgements and in relevant professional guidance.15 ,37–39

Thus, through a combination of legislation, case law and homogeneous practice, what has emerged is a determination of best interests incorporating both factual and subjective elements that is generally case-dependent. For example in the UK, the Children Act 198940 requires those making decisions about a child's welfare to take account of a child's ‘physical, emotional and educational needs’. This has been expanded through case law to define best interests inclusivelyii to include ‘every kind of consideration capable of affecting the decision’,41 a formulation which is reiterated in guidance on genetic testing in children published by the British Society of Human Genetics.6

Guiding principles for determining the child's best interests include the severity of the condition, the extent of any treatment or intervention that can be offered as a result of genetic testing and when symptoms are likely to arise.39 For example, genetic testing may be justified in a child at risk from familial adenomatous polyposis before they are competent to make a fully informed decision, on the basis that a positive test result would indicate the need for early detection and removal of precancerous polyps through screening to prevent malignant cancers from forming in late childhood.42

The second prevailing principle that has emerged in predictive genetic testing is that children should be involved as much as possible in decision-making which affects them.7 ,43 Thus, the preferred option is to preserve autonomy by postponing genetic testing until the young person has sufficient competence to make their own decision.6 In practice, this criterion is regarded as particularly important if there is a lack of consensus about the utility of testing where consequences might be profound. An example is testing for monogenic conditions (such as Huntington's disease) for which no effective treatment is available, and in which a substantial majority of adults who are offered diagnostic testing decline it after suitable counselling.25

Thus testing children for low-risk variants for common cancers might seem to have little justification given that breast, ovarian and prostate cancers are unlikely to develop before children are old enough to make decisions for themselves. Imposing a systematic genetic screening programme involving children could be regarded as depriving them of the opportunity of making their own decisions and of their right ‘not to know’ their genetic status. Conversely, the failure to generate and use individual genetic variant information through targeted population screening early in life could deprive the same people of the opportunity to make informed, autonomous lifestyle choices that might affect their later cancer risk, such as the use of hormone-based contraceptives or smoking, particularly once they become competent to make their own decisions from teenage years.

Parents might also argue that lack of knowledge of their child's genetic status deprives them of the opportunity to make informed choices about their children and their lifestyles, which potentially thwarts their own autonomy interests and those of their young child (for whom they act as proxy). The emphasis on preserving the child's autonomy to the detriment of other factors also underplays and undermines other important family dynamics that promote intimacy, solidarity and communication within the family.44 Thus for population genotyping, a less individualistic, population-based approach might be more determinative, rather than using a normative framework predicated upon best interests and maximising individual autonomy.

Role of population-based screening criteria in evaluating childhood genotyping for common complex cancers

In many jurisdictions, potential screening programmes are appraised on the basis of criteria which capture population-based measures of utility rather than individual impact. For example, the Wilson and Jungner criteria comprise parameters including the nature of the disease that will be screened for, the acceptability and use of a test, possible interventions and treatments and cost considerations.45 While these criteria have proved useful for policy makers since they were formulated over 45 years ago, various commentators have argued that modifications are needed to take account of the changing nature of genetic susceptibility screening. Although there is emerging evidence of utility and cost-effectiveness for screening populations of children for single conditions such as type 1 diabetes, it is unclear whether even narrowly focused programmes such as these can satisfy population-based criteria.46 ,47 Increasing use of powerful technologies for screening such as exome sequencing, and simultaneous testing for multiple conditions via many hundreds of genetic variants, has the potential to blur these conventional distinctions between ‘screening’ and ‘testing’48 ,49 and also raises questions about how these population-based screening criteria, which are defined in terms of their relevance to a single condition or disease state, are relevant, and can be systematically applied, to multiple conditions.17 ,49

Thus genotyping children for the purpose of personalised screening for common cancers seems to challenge frameworks that evaluate both individual and population-based justifications.

Concluding comments

A number of drivers are converging to support the development of personalised screening initiatives in children and young people. Modelling from the COGS project has demonstrated the technical feasibility of personalised screening approaches,2 and the case for targeting neonates and young children seems to be strengthened by the existence of state-sponsored population screening initiatives, a burgeoning market for genomic information and commercial incentives in the form of multiplex testing technologies, which enable simultaneous testing for multiple conditions.

However, some important caveats remain. Despite increasing granularity of findings, such that a length of DNA may be reliably and robustly sequenced identifying a string of bases, the interpretative step of understanding the functional impact of a DNA sequence across a person's lifetime, remains extremely challenging. Faced with these formidable technical difficulties and the impact of multiple intervening risks,50 communicating these benefits as well as the uncertainties as part of the consent process is vital; although results may be inherently speculative, they could still provoke stigmatisation or discrimination. Logistical factors, including the provision for robust data storage and safeguarding confidentiality, are also highly relevant.

Aside from these technical considerations, it remains unclear whether the potential benefits to a minority of those undergoing population-based targeted genotyping confer sufficient justification for exposing all children to susceptibility sampling and testing. As well as further ethical debate, quantification of the benefits requires empirical research which can examine these issues systematically.7 Research questions include the extent to which knowledge of genotypic or environmental risks prompts changes in parental practice or behaviour; how these behaviour changes cause improvements in health (through modification of tractable risk factors or to prevent or forestall the development of a condition); whether the effects might be long lasting (for which longitudinal studies will be needed); how a population-based approach might provide greater coverage of the ‘at-risk’ population; access to testing and distributive justice issues, as well as the need to ensure the acceptability of personalised screening programmes to the wider public without undermining public trust in existing programmes.51–53

Population-based screening programmes that use genotyping to stratify the population according to risk, highlight the tensions between population-centric and individualised approaches. This suggests a need for a composite normative framework, incorporating elements of both, in which there is less emphasis upon the protection of autonomy. This would provide a more robust basis for the implementation of childhood genotyping within population-based screening programmes.

To summarise, population-based genotyping and personalised screening for common cancers informed by the systematic sampling of neonates, children and young people is now technically feasible. Despite the fact that CGVs for common cancers are variably expressed, weakly penetrant and weakly determinative of disease (since other factors may intervene over an individual's lifetime), personalised approaches incorporating genotyping potentially offer improved health through more effective targeting of screening and treatment, and in reducing associated risks. On this basis, we expect that, over the next decade, there will be calls to integrate genotyping within existing neonatal screening programmes to facilitate personalised screening for common cancers and many other chronic conditions.

Existing normative frameworks used to evaluate predictive genetic testing of children within clinical genetics settings emphasise the importance of preserving future autonomy. This seems disproportionate when considering most CGVs for common cancers—suggesting that a new ethical paradigm needs to be developed. Two other factors are pre-eminent. First, the complexity of the risk assessment reinforces the need for a diverse group of stakeholders to be involved in policy formation, and for serious account to be taken of empirical work that measures public demand for such testing. Second, as the potential for discrimination and stigmatisation remains great, developments of this sort should take place within a context of sustained efforts to improve genetic education and genetic literacy within the wider population.

References

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Footnotes

  • Contributors AEH developed this work and drafted the paper. HB, SC, NH, NP and PP contributed to the process of development and to subsequent revisions. All authors read and approved the final paper.

  • Funding This work was supported by funding from the European Community Seventh Framework Programme under grant agreement 223175 (HEALTH-F2_2009-223175). The funding source had no role in the writing of this report or the decision to submit the paper for publication for which all authors had responsibility. All authors except PP and NP are employed by the PHG Foundation, which is the working name of the Foundation for Genomics and Population Health, a charitable company registered in England and Wales, charity No. 1118664 company No. 5823194.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • i Clinical utility can be defined as an assessment of the risks and benefits resulting from using a particular test and the likelihood that the test will lead to an improved overall outcome. (http://www.phgfoundation.org/pages/resources/glossary.htm accessed on 29 May 2012).

  • ii In a case concerning the withholding of life-sustaining treatment, this included ‘medical, emotional, sensory (pleasure, pain and suffering) and instinctive (the human instinct to survive) considerations’.

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