Independent report

Child-family screening for familial hypercholesterolemia: ethical issues

Published 10 February 2022

1. Executive summary

In 2020, the UK National Screening Committee (UK NSC) set up an ethics task group to carry out an analysis of the ethical issues raised by child-family cascade screening for familial hypercholesterolemia (FH). The group included members with expertise in ethics, paediatrics, clinical genetics, sociology, primary care and public health and a patient representative.

The purpose of the work was to:

• inform, alongside reviews of research evidence, future UK NSC recommendations on childhood or child-family cascade screening programmes for FH
• test out a new UK NSC ethical framework and ethical analysis process

The findings were also intended to inform the direction of a planned NHS England and Improvement (NHSEI) service evaluation of child-family cascade screening for FH in 1 to 2 year olds.

The analysis identified a number of ethical questions raised by this screening strategy. Many of these apply more broadly to childhood screening programmes that involve genomic testing. These included how the benefits of screening for the wider family should be taken into consideration in decisions about childhood genomic screening and whether it is acceptable to have a significant time delay between a childhood screening test and the age of eligibility for effective interventions.

The ethics task group considered these and other questions with reference to an ethical framework for screening comprised of 4 principles. These are to:

1. Improve health and wellbeing.
2. Treat people with respect.
3. Promote equality and inclusion.
4. Use public resources fairly and proportionately.

The group held meetings with stakeholders to inform its discussions.

This report presents a discussion of the ethical questions identified and sets out considerations for the future, including:

• the primary aim of screening for FH in childhood should be to confer health benefits during childhood to children with FH who screen positive for FH
• secondary benefits of childhood screening, such as improving the health of others with FH through cascade testing within families, can strengthen the case for screening and may be relevant to determining the most appropriate age for screening
• screening should ideally take place as close as possible to the point and time at which effective interventions can be initiated in screened individuals, although there may be practical factors that could justify a delay
• it is important that appropriate resource, time and attention is paid to ensuring parents make informed, considered choices about screening
• evidence on the potential benefits and harms of early dietary intervention and an understanding of the views and experiences of families with FH and families eligible for screening will be important to assessments of FH screening in 1 to 2 year olds
• the overall reach and impact on health and wellbeing of any strategy or combination of strategies that aim to increase the identification of people with FH in the general population should be considered, evaluated and compared

2. Familial hypercholesterolemia (FH)

FH is a condition where the body has a high amount of cholesterol. The build-up of cholesterol can block blood from being supplied to the heart and other areas of the body. This causes cardiovascular problems, including heart disease, which can lead to serious illness and death.

There are 3 principal genes in which variants can cause FH. These variants can be passed on through either the mother or father (heterozygous FH) and in some rare cases through both (homozygous FH). The prevalence of heterozygous FH in the UK population is believed to be between approximately 1 in 250 and 1 in 500. Homozygous FH is a much more severe form of FH and much rarer, affecting around 1 in 300,000 people.

Adults with FH are offered a high-intensity statin alone or in combination with other cholesterol-lowering medication as the initial treatment. The aim is to reduce cholesterol levels by at least 50%. Adults with FH are likely to take medication for the rest of their lives. Cholesterol-reducing medication is recommended for young people with FH from the age of 8 to 10 years onwards. All people with FH should be offered nutritional advice and smoking cessation support.^{[footnote 1]}

Current NICE guidance recommends that doctors carry out cascade testing to identify affected biological relatives of people with a diagnosis of heterozygous FH. However, it is estimated that only a small proportion of people with FH in the UK population have been identified.^{[footnote 2]}

3. NHSEI service evaluation of cascade screening

The 2019 NHS long term plan aims to increase the proportion of those identified as having heterozygous FH from 7% in 2021 to 25% over 5 years. NHSEI plans to deliver this through:

• child-family cascade screening
• GP searching of adult health record data

NHSEI plans to run a service evaluation of a child-family cascade screening programme for FH for 18 months across 3 to 5 academic health science networks (AHSNs). There are 15 AHSNs across England, each serving a different region. NHSEI expects to follow the service evaluation with a national roll out to all 15 AHSNs, subject to NHS funding support.

The service evaluation will involve screening 1 to 2 year-old children for FH when they are taken to their GP surgery for routine vaccination. Information will be sent to the family in advance and verbal consent will be sought from the parent or carer at the appointment. A blood sample will be taken by heel prick and used to obtain a total cholesterol measurement.

Where a child is found to have high cholesterol, a further blood sample will be sent for FH genetic testing. The 2 blood samples will be taken at the same time so there is no need for a repeat visit. Children with particularly high cholesterol and no FH genetic variant will have a repeat cholesterol test 3 months later.

The child will be offered lipid testing and a specialist referral if they are found to have:

• high cholesterol (1.35 multiples of the median (MoM) – approx. 6 millimoles per litre (mmol/L)) and an FH genetic variant, or
• 2 very high cholesterol results (1.53 MoM – approx. 7 mmol/L) in the absence of an identified FH genetic variant

The child’s parents and all traceable relatives also will be offered testing for FH, so-called cascade screening.

This strategy is largely based on a study carried out by Wald and colleagues (2016) which evaluated the performance of a phenotypic testing strategy for child-parent screening. The study provides the following justification for screening at age 1 to 2 years:

Screening children at routine immunisation visits, at 1 to 2 years of age, avoids a separate clinic visit and offers screening at a time when parents are particularly receptive to preventing disease in their child. Previous studies showed that the discrimination of cholesterol levels in persons with and those without FH was best at 1 to 9 years of age, with a suggestion that it may be best at 1 to 2 years of age, and was worse at older ages and in neonates.^{[footnote 3]} Screening younger children identifies parents earlier, which enables parents to start statin therapy earlier if needed.^{[footnote 4]}

Ahead of the service evaluation, NHSEI approached the UK NSC for guidance on the information that the UK NSC would find useful for future assessments of child-parent screening for FH at 1 to 2 years of age against the criteria for population screening.

4. UK NSC evidence reviews

The UK NSC assesses the evidence for population screening programmes against 20 criteria for appraising the viability, effectiveness and appropriateness of a screening programme.

Screening for FH in childhood was added to the UK NSC regular review list in 2016. The evidence relating to this topic was updated in 2019 to 2020. At this point the focus of the review was on the performance of the test and the effectiveness of interventions in the child. UK NSC update reviews initially focus on a limited set of criteria, relating to the severity of the condition, the reliability of the test, and the treatment or intervention for people who are diagnosed with the condition. This allows for proportionate consideration of, and a step wise approach to, each topic. The focus on the child in the 2019 to 2020 review was driven by the principle that a health benefit should be gained by the screened individual. The review concluded that:

• there is remaining uncertainty over the optimal screening age (papers discussing screening at 1 to 2 years or 9 to 10 years were reported), the kind of test, and the test thresholds that should be used in a FH screening programme in children
• no evidence was found to inform whether universal screening affects FH-related morbidity or mortality in children compared with no screening
• there is no evidence to inform whether a universal screening programme may be associated with harms in children
• there is a need for consensus on how FH should be diagnosed in the context of a universal screening programme, whether by the existence of FH genetic variants and/or family history indicative of FH, or by raised cholesterol alone, given this is the mediator of cardiovascular risk

This led to the UK NSC recommending against introducing a childhood screening programme for FH in April 2020. The evidence review and associated consultation also highlighted that screening for FH in children aged 1 to 2 raises ethical questions.

In autumn 2020, the UK NSC set up an ethics task group to carry out an analysis of the ethical issues in order to inform its next review of childhood screening for FH. Around the same time, NHSEI made contact with the UK NSC with its plans to evaluate child-family cascade screening for FH in partnership with the AHSNs. Although not research, the service evaluation is an opportunity to gather intelligence relating to the feasibility, effectiveness and appropriateness of population screening for FH, and provided further motivation for the UK NSC to consider the ethical issues raised.

5. UK NSC ethical framework

The ethical principles of health screening are encompassed within the UK NSC’s criteria for assessing the viability, effectiveness and appropriateness of a screening programme. To further clarify and elucidate the overarching goals of screening, the UK NSC recently developed an ethical framework for screening, which is comprised of 4 broad ethical principles. The principles are all equally as important as each other:

1. Improve health and wellbeing.
2. Treat people with respect.
3. Promote equality and inclusion.
4. Use public resources fairly and proportionately.

Deciding how these ethical principles apply in any given situation is unlikely to be straightforward and often there will be a need for balancing across them. The ethical principles can be in tension with each other and create difficult dilemmas, particularly in the balancing of individual and collective interests. For example, there is a standing possibility that public health interventions and restrictions, being designed to serve the collective interest by improving the health and wellbeing of the population, will come into tension with the principle of treating people with respect (this being understood as respecting the interest of individuals in making their own choices in relation to their own health and wellbeing).

It is the task of the UK NSC to consider evidence and views in each case and make judgements, ensuring it works in accordance with the UK NSC values. UK NSC recommendations about screening are always made on a case-by-case basis and involve consideration of alternative options for reducing the effect of the disease on the population.

The ethical issues raised by child-family cascade screening for FH are discussed below in relation to the 4 principles of the UK NSC ethical framework. Our findings are intended to inform future UK NSC deliberations on childhood or child-family cascade screening programmes for FH, alongside reviews of research evidence relating to the condition, the test, effective interventions and the effectiveness of the screening programme.

Our findings are also intended to inform the direction of the NHSEI service evaluation of child-family cascade screening for FH. UK NSC reviews of other kinds of childhood or genetic screening programmes might also be informed by the findings in future.

5.1 Principle 1: improve health and wellbeing

The general purpose of public health screening programmes should be to improve the health and wellbeing of the population. No screening programme should be adopted unless its potential benefits (to health and wellbeing) outweigh any potential harms. The focus should be on the individuals who will be offered screening. If there is a prospect for screened individuals to benefit, the benefits and harms for others and society more broadly can also be taken into consideration. Potential benefits include prevention of death and disease, improvements in physical and mental health, and improved quality of life. Potential harms include unnecessary and harmful tests or treatment, uncertainty of screening results, false reassurance, and increased anxiety. Efforts should be made to reduce any risks of harms.

Unpacking and applying this first principle are not straightforward. Our elaboration of the principle speaks to: who should benefit from childhood screening if the screening is for a genetic condition (including questions about secondary findings and the family as the beneficiary); the timing of screening within childhood; and how the implementation of screening might impact on the potential benefits and harms.

Benefit from childhood screening programmes

Broadly speaking, national and international professional guidance states that childhood screening for genetic conditions usually should be undertaken only when there is potential for health benefit to the child while they are still a child. If the benefits do not accrue until they are older, then it is generally recommended that screening is delayed until the young person can decide for him/herself when, or whether, to be screened.^{[footnote 5]}

Screening children solely with the aim of identifying and treating others (with a particular genetic condition) would risk ‘instrumentalising’ children, or using them solely as a means to others’ ends, which is widely regarded as morally impermissible.

If the primary beneficiaries of childhood genetic screening should be the screened children, identifying other children or adults with FH through cascade testing could be considered a secondary aim of the screening programme. Potentially, benefits accruing to secondary beneficiaries (such as other children or adults) could also be beneficial (especially in a family context) to the primary beneficiary (the child who is screened). Or, at any rate, the consequences for secondary beneficiaries might mean that harm is avoided in relation to the health and wellbeing of the primary beneficiary.

Secondary findings

Much has been written about secondary or incidental findings in genomic testing and screening. Often this refers to findings about other conditions that the child might have, or whether the child is a carrier of a genetic condition.

Some guidance discusses secondary findings relevant to the health of the parents and family. The guidance is generally supportive of returning secondary findings about parents relating to serious conditions for which treatment is available. For example, the European Society of Human Genetics, the Human Genome Organisation, the PHG Foundation and the P3G International Paediatric Platform state in their guidance on genetic testing in children and adolescents:

Parents may also be offered information regarding unsolicited findings that are severe and clinically actionable relevant to their own health.^{[footnote 6]}

The American Academy of Pediatrics and the American College of Medical Genetics and Genomics state in their guidance on genetic testing and screening of children:

Results from genetic testing of a child may have implications for the parents and other family members. Health care providers have an obligation to inform parents and the child, when appropriate, about these potential implications. Health care providers should encourage patients and families to share this information and offer to help explain the results to the extended family or refer them for genetic counselling.

This position is supported by the findings of a recent UK public dialogue on the implications of whole genome sequencing for newborn screening. Participants were clear that the objective first and foremost should be for genome sequencing to benefit the child, but if the information could help the health of their family members, some thought it should be used to do so. Many participants felt that it was in the child’s best interests to help identify a parent at risk of early onset heart disease and take steps to avoid poor health or an early death.

A further kind of secondary finding that could arise in the case of early childhood screening for heterozygous FH is that of homozygous FH. This is a much more severe form of FH and much rarer, affecting around 1 in 300,000 people. Homozygous FH can cause heart disease beginning in the early teen years and sometimes earlier in life. Early diagnosis and treatment can be lifesaving. Identifying young children with homozygous FH through screening for heterozygous FH would have a significant impact on a small number of families.

A family framing

A different framing would be to think about the family unit as the beneficiary of childhood screening, where the primary aim would be to confer health benefits to both the child and their family members.^{[footnote 7]} In this case, the recommended screening strategy would be the one that was best for the whole family, drawing on ideas of solidarity and that we, as a society, are all in it together.

Such a framing might be justified in more than one way. For example, the thinking might be that the members of the family are so closely connected and inter-dependent that they should be treated as a single unit rather than as so many individuals. A young child alone does not present as a party to be screened. Rather, it is the child-with-parent that not only presents physically for screening but also that meets the required elements of processing information before screening, giving consent, receiving the results of the screening and being able to act on them. Moreover, in a case such as FH, the impact of screening, whether the result is positive or negative, will impact (potentially positively but also negatively) on all members of the family, not just on the child itself.

Family screening of this kind does not have parallels among existing screening programmes. The UK NSC screening criteria state:

Evidence relating to wider benefits of screening, for example those relating to family members, should be taken into account where available. However, where there is no prospect of benefit for the individual screened then the screening programme should not be further considered.

A recent review of international evidence on attitudes towards whole genome sequencing as a newborn screening tool found that parents and public groups often held a ‘panoramic’ view of the beneficiaries of newborn screening, incorporating both past and present family members, as well as wider society. The conceptual division between benefits to the screened individual and benefits to the wider family that appears in current UK screening criteria was far less pronounced in the views of these groups, who had a more blended view of familial benefit. It was suggested that genomic knowledge could trigger strategies of preparation (mental and physical), familial communication and support, and a sense of ownership and control over one’s own, and the family’s health.^{[footnote 8]}

The case for positioning the family as the beneficiary of FH screening is bolstered by the fact that screening children creates the possibility that the health of one or more family members will be improved, which is likely to impact on the wellbeing of those with whom they have relationships. For example, a child who is diagnosed with FH through screening might, as a result, have a parent with FH who receives earlier treatment and lives longer, which is likely to benefit the wellbeing of the child. A participant at one of our stakeholder meetings – an adult with FH – expressed the wish that they had been screened and diagnosed as a baby as this could have saved the life of their father who died of a heart attack in his early 40s. Conversely, children who undergo screening and do not have FH will have undergone the screening intervention without enjoying the benefit of improvement to her parent’s health.

In the case of child-family cascade screening for FH, there is a tension between designing a programme that benefits as many people as possible and one that has the health interests of screened children at its heart. It would be wrong to screen children solely for the benefit of others, so there must be potential for children who screen positive to gain reasonably contemporaneous health benefits from screening. However, given that the wellbeing of children is often closely related to the health of their parents and others in their family, potential health benefits to family members can strengthen the case for screening in children.

Potential health benefits for family members also may be relevant to determining the most appropriate age for screening. For this to be taken into consideration, it would be important to consider the potential increase in life expectancy for parents as a result of childhood screening for FH at age 1 to 2 compared to screening at other ages, or to other strategies for identifying people with FH.

If the health of parents and carers or adults more generally is the primary concern, alternative strategies to childhood screening for identifying those at risk should be explored, such as adult screening programmes or primary care interventions (which are indeed being explored by NHSEI in parallel with the proposal to carry out childhood screening). This would avoid children being instrumentalised and the exclusion of some adults from the programme (see below for further discussion on this).

Considerations

The primary aim of screening for FH in childhood should be to confer health benefits during childhood to children with FH who screen positive for FH.

The secondary benefits of childhood screening include the possibility (through cascade testing) of improving the health of others with FH, as well as early diagnosis of children with homozygous FH. Furthermore, the screened child might themself benefit if a parent or carer is less likely to have a premature death. These wider benefits can strengthen the case for screening for FH in children and may be relevant to determining the most appropriate age for screening, but cannot alone provide justification.

Timing of screening

One of the corollaries of our first ethical principle is that we should choose between screening options in whichever way will best serve the health and wellbeing of the person being screened. In the case of screening children for FH, there is a question about whether the screening should be at 1 to 2 years or at another point and time in childhood. According to our first principle, we should assess which timing option will best serve the health and wellbeing of the child, and then act on the best option. However, in this particular case, the application of that principle is not straightforward.

Currently, all national newborn screening programmes in the UK look for serious conditions that manifest in childhood for which there are available, effective interventions that can be initiated promptly and result in health benefits that will be felt in childhood.

Professional guidance recommends that genetic testing and screening should only take place if there is an effective intervention available that can be started in childhood. For example, the American Society of Human Genetics states in its guidance on genetic testing in children and adolescents:

Unless there is a clinical intervention appropriate in childhood, parents should be encouraged to defer predictive or pre-dispositional testing for adult-onset conditions until adulthood or at least until the child is an older adolescent who can participate in decision making in a relatively mature manner.^{[footnote 9]}

The Global Alliance for Genomics and Health states in its guidance on genomic newborn screening:

Publicly-funded universal newborn screening by genomic methods should be limited to diseases that can be diagnosed in the newborn period and effectively treated or prevented in childhood.^{[footnote 10]}

One of the fundamental criteria for population screening is that individuals who are identified as being at risk of developing a condition can be offered an effective intervention. The ethics task group interprets the guidance to mean that screening ideally should take place as close as possible to the point and time at which effective interventions can be initiated.

The findings of a public dialogue on the implications of whole genome sequencing for newborn screening support this position. A clear message from participants was that genome sequencing should be used in newborn screening only to identify conditions that are treatable, in the immediate weeks and months after screening, with medication or other therapies that will save lives or improve children’s health and wellbeing. When discussing FH specifically, several participants talked about the merits of parents knowing that their child has FH, so that they could ensure their child ate healthily and kept an eye on the amount of high fat foods in their diet.

However, there is uncertainty over the benefits and harms of the intervention available to 1 to 2 year olds with FH (dietary and lifestyle advice), leaving a delay of up to 7 years before an effective intervention (statin treatment) can be considered. If providing dietary and lifestyle advice at age 1 to 2 was shown to have significant health benefits for children with FH which were not outweighed by any harms, this would reduce the ethical difficulties of screening at age 1 to 2. A review of the effectiveness of diet management in people with FH found no studies in children age 1 to 2, but highlighted children from 1 to 8/10 years of age as candidates for diet management only, based on successful outcomes of diet management in people with FH in older age groups.^{[footnote 11]}

Designing an effective, feasible and acceptable screening strategy is often a process of compromise and there may be practical factors that would justify a delay between screening and the initiation of treatment. Examples include: if the screening test was shown to be most accurate, less invasive and likely to be offered to more people at the earlier age; if piggybacking onto existing vaccination programmes was shown to have significant advantages; or if the health benefits to the parents were significantly greater if children were screened at the earlier age.

These factors would need to be weighed carefully with the potential harms of a delay between screening and treatment, such as causing unnecessary anxiety to the family before any action can be taken, the risk of children being put on harmful and unnecessary dietary regimes and becoming labelled as ‘patients in waiting’, and any dis-benefit from offering screening at the same time as vaccination.

Understanding the views and experiences of adults and children with FH and the wider public in relation to screening at different ages will be important. In a 2016 study that evaluated the performance of screening for FH at age 1 to 2 years, a total of 11,010 parents approached (84%) agreed to their children’s participation in the study. All the parents who had positive screening results for FH indicated that they thought the screening was worthwhile and none reported negative effects. A range of qualitative studies have looked at the views of childhood FH screening among adults and children with FH, parents and the public. The studies present mixed views among parents, although many were supportive of testing and screening early in childhood. A study among children with FH aged 8 to 18 suggests they were mostly unaffected by the diagnosis.^{[footnote 12]} There is less evidence on the views of parents whose children undergo screening and receive a negative result.

Our own discussions with a small number of people with FH and parents of children with FH found strong support for screening children for FH at the earliest age possible. Parents whose children had been diagnosed with FH as babies had valued the opportunity to initiate a diet low in saturated fats before eating preferences and habits had become instilled and difficult to change. Diet, treatment and hospital appointments had all become part of normal life in the families we spoke to who had had an early diagnosis.

Considerations

Screening ideally should take place as close as possible to the point and time at which effective interventions can be initiated in screened individuals.

There may be practical factors that could justify a delay between screening and effective interventions, but these would need to be carefully weighed against any potential harms.

Evidence on the potential benefits and harms of early dietary intervention and an understanding of the views and experiences of families with FH and families eligible for screening will be important to assessments of FH screening in 1 to 2 year olds.

Impact of screening on benefits and harms

The ethical acceptability of any screening programme often rests on practical factors related to implementation of screening which can affect the balance of benefits and harms.

The UK NSC’s criteria for population screening programmes state that there must be adequate staffing and facilities available, evidence-based information should be made available to participants, and clinical management of the condition should have already been optimised.

Many of the stakeholders we met during this review emphasised the importance of ensuring adequate genetic testing capacity and appropriate support and counselling for individuals and families following a positive FH screening test and diagnosis, including for children as they grow up and can begin to understand their diagnosis. Effective and appropriate communication processes for contacting relatives will also need to be in place.

Research with members of the public supports this view. For example, those who took part in a deliberative workshop in Australia set out a number of conditions they felt needed to be met for child-parent cascade screening for FH. These included that there should be an FH specialist involved and that there are clear, standardised clinical pathways for those diagnosed with FH.^{[footnote 13]} Participants of the UK NSC’s public dialogue on the implications of whole genome sequencing for newborn screening were clear that genetic counselling and mental health assistance should be available for those who receive a confirmed diagnosis to help with both an understanding of the health condition and to provide emotional and psychological support.

Questions were raised by some of the clinicians we met about whether the NHS currently has the resources, skills and capacity to deal with a significant increase in FH testing and to offer the support that families with a diagnosis of FH will need.

For children age 1 to 2, initially the support provided will focus on providing dietary and lifestyle advice to families. To be effective, family eating interventions must be practical and accessible for parents. A recent review of healthy eating interventions found most did not lead to significant long-term behaviour change, even when delivered to families in the home environment.^{[footnote 14]}

A 20-year Finnish study explored the effects of providing individualised dietary counselling to families with young infants recruited through a baby-well clinic. Dietary counselling was provided at least biannually beginning at 8 months until 20 years of age. They found that children who had met dietary targets relating to fibre intake and the quality of dietary fat had lower concentrations of cholesterol. However, the proportion of participants who succeeded in achieving the dietary target was relatively low, varying from 5% to 32%.^{[footnote 15]} Dietary interventions might be more or less successful in families with a diagnosed medical condition. Among children registered on the UK paediatric FH register, the prevalence of being overweight was similar to the general population, but the prevalence of obesity was significantly lower.^{[footnote 16]}

It will be important to assess the effect of any interventions initiated in screen-positive individuals using good proxy measures for the desired outcome, such as sustained healthy eating behaviour, where necessary.

The impact of information provided to families whose children have cholesterol levels that prompt a genetic test, but which is negative, should also be considered. There is the possibility that this could have a demotivating effect on a family’s adherence to a generally healthy diet.

Considerations

The way in which child-family cascade screening for FH is implemented in the NHS will impact on the balance of benefits and harms and, consequently, the ethical acceptability of the screening programme.

5.2 Principle 2: treat people with respect

People’s rights, wishes and feelings as individuals should be respected. This involves enabling people to make informed choices about screening that align with their personal values, and acknowledging the role that relationships with family members and others can play. People’s choices about screening must be respected and supported. Where screening is offered to people who are not able to make choices for themselves, those who make choices on their behalf should be appraised of the balance of benefits and harms to the screened individual. Policy decisions about screening programmes should take account of the views of those affected and the reasons for policy decisions should be clearly communicated.

Informed choice

Genetic screening in young children removes the opportunity of the future person to make their own choices about genetic testing. Professional guidance states that this opportunity should not be denied to them without good reason.^{[footnote 17]} Screening children in order to identify and treat important childhood conditions (as judged by frequency and/or severity) is widely agreed to be a justifiable reason for forfeiting the child’s future choices, even though screening would not impact on most children’s interests.

In childhood screening, parents and carers are asked to consent for their child to undergo screening. Consent from only one parent is sufficient. In the case of a child-family cascade screening programme that involves genetic testing, parents and carers would be asked to consent, potentially, to receiving results relevant to their child, themselves, the child’s other parent, and other family members and biological relatives.

Undergoing screening could lead to decisions about starting lifelong statin treatment and might give rise to unexpected information relating to paternity. Consenting to screening would also confer certain responsibilities on families. For example, parents could be expected to follow dietary and lifestyle advice if their child is found to have FH, and to inform their child about their screening result when they are old enough to understand it.

There might be cases where the parent wishes to consent to their child being screened, but not to cascade testing on themselves, thereby exercising their ‘right not to know’.^{[footnote 18]} They might wish to undergo screening themselves but not consent for their child to be screened.

Given these and other potential implications of undergoing screening for FH, it is important that appropriate resource, time and attention is paid to ensuring parents and carers make informed, considered choices about FH screening. Given that we know that childhood screening tests are often seen by parents as routine or automatic,^{[footnote 19]} steps need to be taken to ensure that parents are alerted to the fact that their choices about FH screening are neither routine nor automatic. In the context of a service evaluation, it should be made clear to parents and carers that they are not taking part in research.

The UK NSC’s public dialogue on the implications of whole genome sequencing for newborn screening highlighted the importance and complexity of consent in this context. Participants were concerned about the potential psychological and emotional impacts on parents and families of receiving uncertain results or a diagnosis, and the provision of support to deal with this was seen as a priority. Participants also emphasised that 21st century families come in many forms and that any screening programme must cater to the needs of children who, for example, have been adopted or where donor eggs or sperm have been used.

The concept of ‘relational autonomy’ is gaining prominence in conversations about consent in research and clinical practice. This refers to the way in which people’s identities, needs and interests are shaped by their relationships with others. Proponents of the concept suggest “Relational autonomy does not require the patient to suffer harm in order to respect the preferences of a third party [such as a family member], but rather to understand those preferences and take them into account.”^{[footnote 20]} The concept of relational autonomy has relevance in the case of FH child-family cascade screening, where the child and the parents have interests both as individuals and as part of a family.

Participants of the public dialogue talked about how a decision to have a child screened using whole genome sequencing should be made with the wider family in mind. Some worried that this would make the consent process more complex and burdensome for the parents. They wouldn’t just be consenting to something that would affect their child, but also potentially their wider family. The impact on the wider family’s mental health was a particularly strong concern.

It would be helpful to evaluate the extent to which parents and carers who take part in the NHSEI service evaluation have made an informed choice, whether they feel the choices on offer were acceptable, and how their relationships with others and family interests shaped their choices. Measures of informed choice have been developed and tested in other screening contexts, although these have been subject to criticism.^{[footnote 21]}

Asking parents to give proxy consent could be avoided if screening was offered to older children and adolescents at a point and time when they could take part in the consent process. Gillick competence is a term used in medical law to decide whether a child under 16 years of age is able to consent to their own medical treatment without the need for parental consent. The age at which statin treatment can begin for the majority of children with FH – age 8 to 9 years – is likely to be too young for the child’s choices about screening to be valid. However, children and young people of this age can and should be involved as much as possible in decisions about their healthcare, even when they are not able to make decisions on their own. The possibility of involving children in decisions about screening tests provides a reason to conduct screening at an older age, and this should be weighed with other factors under consideration.

Considerations

Given the potential implications of screening for FH, it is important that appropriate resource, time and attention are paid to ensuring parents make informed, considered choices about screening. The possibility of involving children in decisions about screening tests provides a reason to conduct screening at an older age, and this should be weighed with other factors under consideration.

Patient confidentiality

We concluded above that improving the health of relatives with FH through cascade testing within families is a potential secondary benefit of, and can strengthen the case for, childhood screening for FH. In order to maximise these secondary benefits, effective and appropriate communication processes for contacting relatives will need to be in place. These should take into account issues raised by the disclosure of results for patient confidentiality, which are common in genetic testing contexts and in the management of heritable conditions.

Guidance by the General Medical Council for doctors on confidentiality in relation to disclosing genetic and other shared information states:

Most patients will readily share information about their own health with their children and other relatives, particularly if they are told it might help those relatives [..].

If a patient refuses to consent to information being disclosed that would benefit others, disclosure might still be justified in the public interest if failure to disclose the information leaves others at risk of death or serious harm. If a patient refuses consent to disclosure, you will need to balance your duty to make the care of your patient your first concern against your duty to help protect the other person from serious harm.

It has been further argued that, whilst a clinical diagnosis is confidential, the discovery of a familial factor that led to a diagnosis should be available for use in depersonalised form by health professionals to inform the testing and clinical care of other family members.^{[footnote 22]}

However, balancing a doctor’s duty of care is not always straightforward. In March 2020, a woman sued her father’s doctors because they did not inform her of her risk of Huntington’s disease. Doctors asked the father several times whether they could tell his daughter that he had been diagnosed but the father was adamant that the daughter should not be told. The woman later found out she carries the Huntington’s disease genetic variant, and that her child has a 50% chance of also being affected. The judge found that the doctors had conducted the balancing exercise as required, and so had not breached their duty of care to the woman.

Even if a person consents to information being shared with family members, it might prove difficult to do so in practice. As with the sharing of any genetic results, family members might be difficult to contact or trace because the child or parent is adopted, if children have been conceived using donor gametes, or if family members reside outside the UK. Issues might also arise if parents do not engage with the healthcare system or do not communicate their child’s diagnosis to them when they are older.

As we have noted earlier in this report, genetic testing of children can reveal unexpected information about paternity. While a clinician may feel uncomfortable introducing this type of social information into discussions, it can have medical relevance, for example in predicting recurrence risk for future pregnancies.^{[footnote 23]} The possibility of unexpected information about paternity being revealed should be made clear during the consent process.

Considerations

Effective and appropriate communication processes for contacting relatives of screen-positive children should be in place. These should take into account issues of patient confidentiality and situations where relatives will not be easily reached.

The possibility of unexpected information about paternity being revealed should be made clear during the consent process.

5.3 Principle 3: promote equality and inclusion

Screening programmes should not act to increase health inequalities and should aim to reduce them. Access to and delivery of screening should be as equitable and inclusive as possible. Any potential wider consequences of screening for society in the initiation and implementation of screening, both in the short and long term, should be considered.

Inclusion

NHSEI plans to use a combination of strategies to increase identification of people with FH: screening children aged 1 to 2, searching of adult health record data for individuals with raised cholesterol, and cascade testing in families of people diagnosed with FH through either route.

The proposed screening programme presents the opportunity to identify all children with FH age 1 to 2 years, as well as their traceable relatives who have FH. Over several decades, if the test is sufficiently sensitive, this could result in the majority of people with FH being identified, and potentially diagnosed and offered treatment as early as possible. It could also mean that, in future, the chance of 2 people having a child with FH can be determined in advance, with FH testing offered only to children at risk.

In the shorter term, the programme would exclude certain members of the population from the opportunity of having screening. The programme is unlikely to identify:

• children and adults with FH who do not pass on FH to their children (half of affected adults who have one child and a quarter of those who have 2 children)
• children and adults with FH who move into the country after age 1 to 2 years
• children with FH who develop high cholesterol after the age of 1 to 2 years and their relatives
• childless adults with FH (such as 19% of women in England and Wales) who are not related to any screen-positive children

If the primary aim is to identify children age 1 to 2 with FH, then the fact that some adults will not have the opportunity to participate in the screening programme might not give cause for concern. However, if the ultimate aim is to increase health and wellbeing among the general population, it could be argued that identifying older children and adults with FH is a more important and pressing need than identifying babies age 1 to 2 years in the short term, given the risk of heart disease in people with FH increases with age.^{[footnote 24]} Screening older children or adults has the potential to identify more people with FH. Younger children with FH would then also be identified either by cascade testing or by direct testing as they reached the age of screening. However, targeting older children and adults might result in several years of potential cholesterol-lowering treatment to be missed.

Some of the individuals in the list above will be identified though the other arm of the NHSEI plan to increase the identification of people with FH. This will involve searching adult health record data for individuals with raised cholesterol and inviting them for FH testing. All traceable relatives of an FH positive adult will also be offered testing (cascade testing).

Experience in other countries has shown the potential for cascade testing to increase identification rates. The country with the highest rate of diagnosis is the Netherlands where it has been estimated that 71% of people with FH have been diagnosed, followed by Norway at 43% (based on an FH frequency of 1 in 500 in the general population). Both countries use cascade testing strategies rather than population screening.^{[footnote 25]}

In 2017, the National Institute for Health and Care Excellence (NICE) highlighted that current cholesterol level thresholds used in FH cascade testing identifies older people but may miss younger people with FH. Research priorities identified by NICE include:

• use of different thresholds of cholesterol concentrations in primary care records
• the benefits of different search strategies in primary care, for example broadening the number of risk factors defining eligibility for testing
• the benefits of search strategies in secondary care sources
• the efficacy of direct (health system prompted) and indirect (index case prompted) cascade testing

There are many options and factors to weigh up when considering which strategy or combination of strategies should be employed for identifying people with FH.

Considerations

The overall reach and impact on health and wellbeing of any strategy or combination of strategies that aim to increase the identification of people with FH in the general population should be considered, evaluated and compared.

Screening inequalities

Commissioners of any screening programme should be alert to the possibility of inequalities in access to and uptake of population screening. Although there is limited published evidence on inequalities in newborn screening, screening inequalities can manifest themselves at any point along the screening pathway.

Given that the proposal is to offer FH screening alongside the 1 to 2 year vaccinations, inequalities in childhood vaccinations are also relevant. A recent health equity audit of the national vaccination programme found that coverage of routine vaccinations was high but that avoidable inequalities in vaccination still exist within some population groups. It found vaccination coverage could be significantly lower in vulnerable and under-served populations such as people with chronic illness or disabilities, migrants, Travellers and Roma, and looked after children, and suggested extra support may also be needed for children of lone parents, and for parents with large families.

The ethnic mix of 10,095 children age 1 to 2 years who attended for FH child-family cascade screening between 2012 and 2015 as part of a research study has been compared with the ethnic mix recorded in the Office for National Statistics (ONS) census data for a similar age group (0 to 4 years) at a similar point in time, based on a survey of 3,496,750 children. Similar ethnic group proportions were found between the 2 surveys suggesting there were not significant inequalities in those accessing screening. However, there were differences among specific groups. In particular:

• 3% of the screened children were Black compared to 5% of the general group
• 7.2% of the screened children were Asian compared to 10% of the general group
• 4.8% of the screened children were of ‘other ethnic group’ compared to 1.4% in the general group^{[footnote 26]}

NHS commissioners have a duty to have regard to the need to reduce inequalities between patients in access to services that they commission. The national screening inequalities strategy developed by Public Health England sets out its professional and legal commitment to reduce inequalities and the ways in which inequalities in screening can be addressed. The strategy recommends the identification of screening inequalities, designing screening pathways that take account of the needs of people less likely to engage in screening, and engagement with local communities and eligible screening groups should be undertaken to understand barriers to screening.

Considerations

Moral, legal and professional obligations to reduce screening inequalities should be taken into consideration in the design and implementation of child-family cascade screening for FH.

Wider consequences

Some clinicians we met were very concerned about the potential effect on vaccination uptake if FH screening was piggybacked onto an existing vaccination programme.

The Wald and colleagues (2016) study, which evaluated the performance of child-parent screening for FH, found that screening did not reduce vaccination rates; in fact, they increased. The median rate was 76% in the year before screening and 85% after the second year. However, both these rates are significantly below the national average. The latest figures show that UK vaccine coverage estimates at 24 months for all vaccines offered on or after the first birthday ranged from 91% to 94%. There remains uncertainty about the effect on vaccination uptake of offering screening for FH at the same time as childhood vaccination, particularly in areas where current uptake rates are high.

Considerations

The wider consequences of screening should be considered in the design of any screening programme for FH, such as the effect on vaccination uptake of offering screening at the same time as childhood vaccinations.

5.4 Principle 4: use public resources fairly and proportionately

The entire cost of a screening programme should entail the fair and proportionate use of available public resources. Decisions about screening should have regard to evidence from cost-effectiveness analyses.

Fair and proportionate use of public resources

In 2018, McKay and colleagues published a cost-utility analysis of universal FH screening at age 1 to 2 years.^{[footnote 27]} The analysis compared 7 screening protocol options with no screening. It concluded that a strategy involving cholesterol screening followed by genetic testing and cascade testing was the most cost-effective model. The incremental cost-effectiveness ratio versus no universal screening was found to be £12,480 per quality adjusted life year (QALY).

The economic implications of screening at other ages have not been examined, however the McKay study concluded:

The economic implications of screening at slightly higher ages are likely to be minimal, and screening at such ages could again be linked to other routine childhood healthcare attendances. Vaccination uptake rates indicate that this would be unlikely to have a major impact on screening participation, at least in the UK. A key issue for decisions about optimal screening age is the outstanding uncertainty around the optimal age for treatment initiation. It remains possible this may be around the time of school entry, or earlier. Once better understood, screening at an age that limits the need for ongoing review during a period of limited treatment options (when LMT [lipid modifying therapy] is not effective and/or licensed) – and the potential associated anxiety – may be preferred.

It would be helpful to understand the trade-offs between different screening strategies in a broader sense. For example, would screening at age 1 to 2 result in significantly improved health outcomes for the relatives of children of FH when compared to screening older children? Also, would improvements in cascade testing impact on estimated gains from universal screening?

A further consideration when designing a population screening programme for FH is whether it is capable of being expanded to other screening tests that the NHS might wish to offer in future. The government’s strategy for genomic healthcare, for example, suggests that the UK is well placed to lead the world into the new era of genomic prevention. The strategy commits the government to exploring whether and how genomic sequencing should be implemented for newborns and sets out ambitions for a new generation of risk prediction tools that could be used in adult screening in future. Ensuring as far as possible that the infrastructure and skills developed for a screening programme on FH could be utilised for other screening tests in future would help with the efficient use of public resources. Whether genomic screening is preferred in the newborn period or in young persons able to give consent will need to be considered.

Considerations

It would be helpful to understand further the trade-offs between screening at different ages. Ensuring as far as possible that the infrastructure and skills developed for a screening programme on FH could be utilised for other screening tests in future would support the efficient use of public resources.

6. Summary of considerations

This review has discussed the ethical issues raised by child-family cascade screening for FH in relation to the 4 principles of the UK NSC ethical framework. Our findings are intended to inform future UK NSC deliberations on childhood or child-family cascade screening programmes for FH, alongside reviews of research evidence relating to the condition, the test, effective interventions and the effectiveness of the screening programme. Our findings are also intended to inform the direction of the NHSEI service evaluation of child-family cascade screening for FH.

6.1 Improve health and wellbeing

The primary aim of screening for FH in childhood should be to confer health benefits during childhood to children with FH who screen positive for FH.

The secondary benefits of childhood screening include the possibility (through cascade testing) of improving the health of others with FH, as well as early diagnosis of children with homozygous FH. Furthermore, the screened child might themself benefit if a parent or carer is less likely to have a premature death. These wider benefits can strengthen the case for screening for FH in children and may be relevant to determining the most appropriate age for screening, but cannot alone provide justification.

Screening ideally should take place as close as possible to the point and time at which effective interventions can be initiated in screened individuals.

There may be practical factors that could justify a delay between screening and effective interventions, but these would need to be carefully weighed against any potential harms.

Evidence on the potential benefits and harms of early dietary intervention and an understanding of the views and experiences of families with FH and families eligible for screening will be important to assessments of FH screening in 1 to 2 year olds.

The way in which child-family cascade screening for FH is implemented in the NHS will impact on the balance of benefits and harms and, consequently, the ethical acceptability of the screening programme.

6.2 Treat people with respect

Given the potential implications of screening for FH, it is important that appropriate resource, time and attention is paid to ensuring parents make informed, considered choices about screening.

The possibility of involving children in decisions about screening tests provides a reason to conduct screening at an older age, and this should be weighed with other factors under consideration.

Effective and appropriate communication processes for contacting relatives of screen-positive children should be in place. These should take into account issues of patient confidentiality and situations where relatives will not be easily reached.

The possibility of unexpected information about paternity being revealed should be made clear during the consent process.

6.3 Promote equality and inclusion

The overall reach and impact on health and wellbeing of any strategy or combination of strategies that aim to increase the identification of people with FH in the general population should be considered, evaluated and compared.

Moral, legal and professional obligations to reduce screening inequalities should be taken into consideration in the design and implementation of child-family cascade screening for FH.

The wider consequences of screening should be considered in the design of any screening programme for FH, such as the effect on vaccination uptake of offering screening at the same time as childhood vaccinations.

6.4 Use public resources fairly and proportionately

It would be helpful to understand further the trade-offs between screening at different ages.

Ensuring as far as possible that the infrastructure and skills developed for a screening programme on FH could be utilised for other screening tests in future would support the efficient use of public resources.

7. Ethics task group

The ethics task group was set up in autumn 2020. The group aimed to:

• advise the fetal, maternal and child health reference group of the UK NSC by carrying out an analysis of the ethical and social issues raised by screening children at different ages for evidence of FH in them and their families
• test out a new UK NSC ethical framework and ethical analysis process for screening questions that raise ethical issues

This report outlines the findings of the first of these aims. The ethics task group did not consider NHSEI’s plans for a service evaluation as a research ethics committee might. Rather, it explored a range of potential ethical questions raised by child-family cascade screening for FH with NHSEI’s specific plans for a service evaluation in mind.

7.1 Membership

The members were appointed by the chair of the UK NSC to create a combination of expertise and knowledge appropriate for the aims of the group. Existing members of the UK NSC and its reference committees were considered first. Where there were gaps in required expertise, individuals who were not existing members were appointed. All members declared any relevant personal and non-personal interests at the time of their appointment and agreed to act in the spirit of the 7 principles of public life set out by the Committee on Standards in Public Life.

The members were:

Roger Brownsword (Chair)

Professor of Law, King’s College London and Member of UK NSC

Sunil Bhanot

GP and Member of Adult Reference Group of the UK NSC

Louise Bryant

Professor of Psychological and Social Medicine, University of Leeds and Member of UK NSC

Angus Clarke

Clinical Professor, Division of Cancer and Genetics, Cardiff University and All Wales Medical Genetics Service

Sharon Hillier

Director of the Screening Division of Public Health Wales and Chair of the Fetal, Maternal and Child Health Reference Group of the UK NSC

Katherine Robertson

Patient and family representative

Graham Shortland

Consultant Paediatrician with a special interest in Inherited Metabolic Diseases, Children’s Hospital for Wales, University Hospital of Wales, Cardiff and Member of UK NSC

Anne-Marie Slowther

Professor of Clinical Ethics, Warwick Medical School and Member of UK NSC

7.2 Methods

The ethics task group met virtually 4 times between December 2020 and May 2021. Their discussions were informed by the ethics literature and international professional guidance on childhood screening and genomic testing.

A number of meetings with stakeholders were held, including with:

• individuals with FH, parents of children with FH, and representatives of organisations that support people with FH
• healthcare and other professionals who may be involved in FH screening and the provision of follow-up care and support
• ethics and law experts
• individuals leading the NHSEI / AHSN service evaluation on child-family cascade screening for FH

The findings of a public dialogue on the implications of whole genome sequencing for newborn screening were also considered by the ethics task group, given their relevance to the questions raised by child-family screening for FH. The public dialogue was a collaboration between the UK NSC, Genomics England and Sciencewise that took place between October 2020 and July 2021.

An early draft of this report was reviewed by the fetal, maternal and child health sub-group of the UK NSC and individuals who had participated in the stakeholder meetings, including: Jules Payne, Chief Executive of Heart UK; Chris Byrne, Professor Endocrinology and Metabolism at University of Southampton and Southampton General Hospital; and John Coggon, Professor of Law at University of Bristol.

8. Acknowledgements

The UK NSC is grateful to everyone who contributed to the work of the ethics task group, including Dermot Neely, Consultant in Clinical Biochemistry and Metabolic Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust, and Julia Newton, Medical Director, Academic Health Science Network – North East and North Cumbria.

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