J of Inher Metab Disea 2023 Spiekerkoetter Genomic Newborn Screening Are We Entering A New Era of Screening

Received: 28 February 2023 Revised: 1 June 2023 Accepted: 13 June 2023
DOI: 10.1002/jimd.12650
REVIEW
Genomic newborn screening: Are we entering a

new era of screening?
Ute Spiekerkoetter 1 | David Bick 2 | Richard Scott 2 | Henrietta Hopkins 3 |

4 5 6
Tanja Krones | Edith Sky Gross | James R. Bonham
1
Department of Pediatrics, Adolescent
Medicine and Neonatology, Faculty of Abstract
Medicine, University Children's Hospital, Population newborn screening (NBS) for phenylketonuria began in the
Freiburg, Germany
United States in 1963. In the 1990s electrospray ionization mass spectrometry
2
Genomics England Ltd, London, UK
3
permitted an array of pathognomonic metabolites to be identified simulta-
Hopkins Van Mil, Coppergate House,
London, UK
neously, enabling up to 60 disorders to be recognized with a single test. In
4
URPP Human Reproduction Reloaded – response, differing approaches to the assessment of the harms and benefits of
H2R and Institute of Biomedical Ethics screening have resulted in variable screening panels worldwide. Thirty years
and History of Medicine, University
on and another screening revolution has emerged with the potential for first
Hospital/University of Zurich, Zurich,
Switzerland line genomic testing extending the range of screening conditions recognized
5
EURORDIS – Rare Diseases Europe, after birth to many hundreds. At the annual SSIEM conference in 2022 in Frei-
Paris, France burg, Germany, an interactive plenary discussion on genomic screening strate-
6
International Society of Neonatal gies and their challenges and opportunities was conducted. The Genomics
Screening, Maarssen, The Netherlands
England Research project proposes the use of Whole Genome Sequencing to
Correspondence offer extended NBS to 100 000 babies for defined conditions with a clear bene-
Ute Spiekerkoetter, Department of
fit for the child. The European Organization for Rare Diseases seeks to include
Pediatrics and Adolescent Medicine,
University Children's Hospital, University “actionable” conditions considering also other types of benefits. Hopkins Van
Medical Center and Faculty of Medicine, Mil, a private UK research institute, determined the views of citizens and
Freiburg, Freiburg im Breisgau, Germany.
revealed as a precondition that families are provided with adequate informa-
Email: ute.spiekerkoetter@uniklinik-
freiburg.de tion, qualified support, and that autonomy and data are protected. From an
ethical standpoint, the benefits ascribed to screening and early treatment need
Communicating Editor: Areeg
El-Gharbawy
to be considered in relation to asymptomatic, phenotypically mild or late-onset
presentations, where presymptomatic treatment may not be required. The dif-
ferent perspectives and arguments demonstrate the unique burden of responsi-
bility on those proposing new and far-reaching developments in NBS
programs and the need to carefully consider both harms and benefits.
The manuscript summarizes plenary lectures from David Bick, Henrietta Hopkins, Tanja Krones, and Edith Gross at the SSIEM 2022 symposium in
Freiburg, Germany.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
778 wileyonlinelibrary.com/journal/jimd J Inherit Metab Dis. 2023;46:778–795.

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SPIEKERKOETTER ET AL. 779
KEYWORDS
actionable conditions, challenges and opportunities of genomic newborn screening,
EURORDIS, Genomics England, metabolic diseases, metabolic newborn screening, whole
genome sequencing
1 | INTRODUCTION of Muir Gray made in 2008 “All screening programmes

do harm, some do good as well and of these some do
It has been more than 60 years since the pioneering work more good than harm at reasonable cost.”7 While there is
of Robert Guthrie who provided a simple and inexpensive little doubt that highly targeted and well-organized
means of detecting phenylketonuria (PKU) in asymptom- screening linked to effective treatment can offer huge
atic babies shortly after birth allowing whole population benefits, it is also true that mass screening of asymptom-
newborn screening for PKU to begin in Massachusetts atic individuals will lead inevitably to false positive
and Oregon in the United States in 1963.1 This life- results, increased phenotypic heterogeneity in the condi-
changing intervention, linked to effective dietary tions recognized and uncertainty for families when the
treatment, provided the opportunity for those with an threshold to treat is not achieved and yet the test results
otherwise poor outlook to enjoy a good quality of life. In obtained cannot be considered entirely normal.
fact, Guthrie provided us with not just a test for PKU, but Assessing the balance between these potential harms
also a robust and reliable means of sample collection, the caused to families who believed their child to be well
dried blood spot card, allowing samples to be transported before the screening result turns out to be a false positive
easily to regional testing centers and this in turn provided or for whom the need for treatment may be uncertain,
the basis for the newborn blood analyte screening that when set against the undoubted life-changing benefit for
we recognize today. It was not long before additional dis- those babies who can receive early and effective treatment
orders such as congenital hypothyroidism, galactosemia, for a classical form of the condition, is a very difficult task
sickle cell anemia, congenital adrenal hyperplasia, and and it is unsurprising that different national bodies and
others were added to the list and newborn screening committees have formed differing conclusions.
spread quickly from the United States to Europe and fur- Overall, newborn screening is part of Preventive Pedi-
ther afield. Today around 38 million babies each year are atric Health Care programs, which are well-established
offered newborn screening in some form, around 30% of and well-accepted in many countries worldwide and con-
those born in the world each year.2 sidered essential for child health.8 However, it is certainly
While incrementally, new tests and conditions were not the case that more screening automatically means
added, during the 1970s and 1980s, a new test needed to better screening and our understanding of the harms
be developed each time a new condition was to be con- resulting from screening and how best to avoid these,
sidered. This changed in the 1990s when a new and dis- remain poorly understood while at the same time the
ruptive technology, electrospray ionization linked to long-term outcome studies to allow us to assess the bene-
tandem mass spectrometry was introduced.3 This impor- fits for patients identified by screening are also sorely
tant methodological advance opened the possibility to lacking. Indeed, internationally agreed case definitions
add up to 60 additional disorders to newborn screening based on standardized confirmatory testing, as a basis for
in a single test and countries began to consider carefully national or international comparison are frequently
which of these disorders should be included. absent for many of the conditions included with our
While the hugely influential Wilson and Jungner cri- national newborn screening panels.
teria published in 1968,4 shortly after newborn screening In recent years the number of metabolic diseases for
began, offered an invaluable guide to selection, the way which effective treatment is now available has been rising
in which these criteria have been interpreted and the evi- rapidly. According to a recent review, 116 of the more than
dence required to ensure that they are satisfied vary con- 1400 known metabolic diseases were treatable in 2021,
siderably around the world. While in the United States, and 44 of these were identified only in the last 8 years.9
36 primary and 26 secondary targets are routinely There are other references listing more than 700 treatable
screened in most states,5 the picture in Europe is much genetic conditions that appear in childhood.10 Effective
more variable with the number of conditions included genomic therapies for historically untreatable conditions
ranging from 2 to 40+.6 such as spinal muscular atrophy and metachromatic leu-
This reticence, even in highly developed countries, codystrophy are also being introduced and as a result the
such as France, Germany, and the United Kingdom is need to identify babies early and offer treatment before
perhaps best represented by the widely quoted statement symptoms develop forms a mounting pressure.11
780 SPIEKERKOETTER ET AL.
It is with these important, sometimes contradictory newborn screening, if the screening criteria will still be
drivers, alongside our gaps in understanding of both the met, and whether genomic screening should be targeted
benefits and harms of screening to the public health, that or untargeted.
existing policy must be framed and from which new tech-
nological advances, extending both the range and scope
of newborn screening, must be evaluated. 2 | NEW BORN SC REENING BY
It is therefore unsurprising that the ethics of suggest- WHOLE GENOME
ing that the DNA or parts of the DNA of all babies should SEQUENC I NG – OPPORTUNITIES
be examined shortly after birth to identify the possibility AND CHALLENG ES BY DAVID BICK
that they might benefit from clinical referral is highly AND RICHARD S COTT
contentious. This approach has the ability to offer huge
benefits to a small but growing number of children Newborn screening for treatable, early onset disorders
whose lives could be changed as a result and yet it also has been deployed with great success worldwide.12 Over
carries the potential to increase anxiety and uncertainty the years, the use of new technologies has expanded the
without clear benefit for a number of children and their disorders tested.13 The current Recommended Uniform
families before the child is old enough to consent. Screening Panel in the United States14 includes more
At the annual conference of the Society for the Study than 50 conditions. However, adding disorders to the
of Inborn Errors of Metabolism (SSIEM) in Freiburg, screen is a slow process. Nationwide adoption in the US
Germany, which took place between August 30 and of a new condition averages 9.5 years.15
September 2, 2022, an interactive plenary session and dis- The current UK newborn screening program tests for
cussion on new genomic screening strategies and their nine conditions: sickle cell disease, cystic fibrosis, con-
challenges and opportunities was conducted. genital hypothyroidism, phenylketonuria, medium-chain
Four renowned scientists and experts in the field acyl-CoA dehydrogenase deficiency, maple syrup urine
shared their perspectives on genomic newborn screening disease, glutaric aciduria type 1, homocystinuria, and iso-
and took part in the panel discussion which followed. valeric acidemia.16 The program is well accepted with the
offer of screening accepted by >99% of families. Studies
David Bick provided an overview of the Genomics to evaluate the addition of severe combined immune defi-
England research project, which aims to screen ciency (SCID) screening17 and spinal muscular atrophy
100 000 newborns for treatable monogenic disorders (SMA) screening9 are also underway.
using whole genome sequencing as an adjunct to the Genome sequencing of newborns represents one
current screening program. potential avenue to rapidly expand the number of
Henrietta Hopkins focused on the public view to dis- conditions screened. There is an urgent need to explore
till the collective voices of society on the topic of screening in new settings as there are more than
genomic newborn screening. Importantly, the results 700 childhood-onset conditions and many of them are
of her studies are now helping to inform the plan- treatable.10 Efforts to trial genomic sequencing in new-
ning of the Genomics England project. born screening have been published.18–20
Tanja Krones reflected from the ethical perspective In the United Kingdom use of whole genome
on the assumptions of “P4” medicine (predictive, pre- sequencing (WGS) as an adjunct to the current newborn
ventative, personalized, participatory) and discussed screening has been under consideration for some time.
how to cope with all the available data with respect Over the last several years reports supporting a study of
to variants of unknown significance. WGS in the setting of newborn screening have been
Edith Gross representing EURORDIS in the published.21
European “Innovative Medicine Initiative” project These reports led to a public engagement in 2021
Screen4Care, provided a unique perspective of examining the implications of genome sequencing in
patient organizations when considering the use newborn screening.22 The engagement concluded that “It
of advanced technologies such as artificial intelli- would be acceptable to use WGS to identify a wider set of
gence and genomic testing to shorten the path to conditions than the current NHS newborn screening pro-
diagnosis for rare disease patients. gram if: (1) the conditions impact the infant in early
childhood and (2) there are treatments and interventions
This review, based on these presentations and the fol- to cure, prevent, or slow progression of the conditions.”
lowing joint discussion, seeks to explore public, patient, The report pointed to the potential for WGS in newborn
and professional viewpoints and to examine whether screening to bring health benefits to the rest of the family
these new technologies are feasible and desirable for and the importance of genetic counseling and mental
health assistance for the family receiving a confirmed T A B L E 1 Four principles used to choose genes and conditions
diagnosis. Further, the establishment of a comprehensive in the Genomics England Newborn Genomes Program.
genetic database was recommended to ensure that ethnic Principles used to choose genes and conditions in the
minorities are not disadvantaged as they are at risk to Genomics England program
receiving more uncertain, or less accurate, diagnoses
A There is strong evidence that the genetic variant(s) causes
than the rest of the population from newborn screening. the condition and can be reliably detected. Where
The public engagement acknowledged the research value appropriate, there may be a confirmatory test that can
of the WGS data to deliver improved diagnoses, treat- establish whether or not the child has the condition
ment, and care provided that the information was anon- B A high proportion of individuals who have the genetic
ymized. The report also noted the benefits and risks from variant(s) would be expected to have symptoms that
the use of WGS data throughout the infant's lifetime. would have a debilitating impact on quality of life if left
In 2021, the UK government funded a research study undiagnosed. The impact on quality of life should
through Genomics England to examine the use of WGS consider factors such as the testimony of patients and
families affected including social and environmental
in newborns23 alongside the current newborn screening
factors, and QALYs where available
program.
The study aims to: (1) evaluate the feasibility, utility, C Early or pre-symptomatic intervention for the condition
has been shown to lead to substantially improved
and impact on the NHS of screening for childhood-onset
outcomes in children, compared with intervention after
rare actionable genetic conditions; (2) understand how, the onset of symptoms. The intervention would
with consent, genomic and healthcare data could be used normally be initiated in early childhood (by age 5); and
to enable research to develop new diagnostics and treat- could either cure, delay or modify the course of the
ments; and (3) explore the implications of storing an indi- condition
vidual's genome for use over their lifetime. This will be D Conditions screened for are only those for which the
an ethics-approved research study embedded in the NHS interventions are equitably accessible for all. This
that will include an evaluation of the effectiveness of incorporates input from NHS England and other
genomic screening to support future decisions on relevant clinical and commissioning bodies
whether this should be translated into a routine clinical
service. Care will be taken to undertake the work in close
collaboration with stakeholders and the public taking
into consideration the impact on NHS clinical care path- commissioners, and professional bodies regularly
ways and workforce.24 reviews progress and advises Genomics England. Addi-
The study is funded to screen 100 000 newborns start- tionally expert working groups provide focused advice
ing in 2023. Given the estimate of 1 in 200 children are concerning recruitment, ethics, evaluation, education,
born with a treatable disorder10 it is expected that there workforce training, and condition selection (the condi-
will be 500–1000 screen-positive newborns, assuming a tions framework work group). Regular engagement
number of false positives. with the public and healthcare professionals nation-
The program chose to use WGS as the screening test wide is also underway.
for several reasons. The current short-read sequencing The conditions framework work group was estab-
technology has been used in clinical practice for many lished in fall 2021. Starting with the Wilson and Jungner
years. It can detect most important variant types includ- criteria,4 the work group developed four principles for
ing single nucleotide variants, indels, copy number vari- choosing genetic disorders for inclusion in the list of con-
ants, and structural variants all of which are known to be ditions that will be sought using whole genome sequenc-
involved in rare treatable genetic conditions. Because ing as an adjunct to the current newborn screening
WGS covers 95% of the human genome adding additional program as detailed in Table 1.
genes to the program is straightforward when new treat- More than 700 conditions from the rx-genes.com web-
able disorders are found. Unlike whole exome sequenc- site10 will be considered. Additional disorders suggested
ing where the capture technology continues to develop, by pediatric specialists will also be considered. It is
WGS will have the same advantage for children from the expected that 200–400 genetic disorders will fulfill the
beginning of the study to the end. It is also recognized four principles. These genetic conditions will also be dis-
that the research value of a genome is superior to an cussed with the specialists who routinely care for these
exome. children to confirm that they will be appropriate to report
As a national study, care has been taken to engage in an asymptomatic newborn. Further, all conditions that
with key stakeholders throughout the project.22 An NHS are deemed appropriate by specialists will be evaluated
steering group that includes physicians, patients, by National Health Service England to confirm that an
established clinical care pathway is available across the A recruitment work group is working carefully with
country. The parents will be counseled that genomic new parents and expectant parents as well as nurse–
newborn screening will only include defined conditions midwives to design a recruitment process. Genomics
and that for the conditions included informed consent England plans to introduce expectant parents to the pro-
will be obtained. gram early in the third trimester of pregnancy. Using
As with all screening, it is important to consider the written material, online material, and opportunities for
positive predictive value (PPV) of the test. The test will be one-on-one discussion the program plans to have parents
performed on asymptomatic newborns at birth with sign up before 36 weeks gestation. At birth the care team
results returned at 2 weeks of age. The chance that a will confirm parents' wish to participate at the time that
given newborn will have one of the conditions on the the sample is taken.
screening panel is low. Therefore, the genetic variants All steps in recruitment, sample collection, testing,
returned must be known or presumed pathogenic or and reporting are being co-designed with nurse–
likely pathogenic variants.25 The following example high- midwives, genetic counselors, clinicians, nurses, health
lights the importance of a variant's PPV. For a genetic visitors, and other elements of the NHS to insure a
disorder found in 1 in 10 000 newborns, a variant with a smooth introduction of the research study in the context of
99.5% sensitivity and 99.5% specificity will have a PPV of a busy workforce. Starting with a few NHS hospital trusts
2%. Exactly 98% of cases with the variant will be false the program expects to engage with more than 20 over
positives. A key outcome of newborn genome programs 2 years to collect 100 000 newborn samples in that time
will be to better understand the best approaches to vari- frame. This will require a significant educational effort.
ant prioritization and the observed sensitivity and speci- Working through the important ethical questions is a
ficity of these approaches, which are likely to differ key component of the program.26 Many of the issues are
between conditions. Functional validation of unknown detailed in a report published in September 2022.27
variants will be necessary, particularly in the beginning A consent model has been established. This process
of the program. reflects lessons learned from the 100 000 Genomes Pro-
Some disorders such as cystic fibrosis and spinal mus- ject28 and feedback from the Ethics Working Group, par-
cular atrophy are well studied and are likely to have high ent interviews, the NHS Newborn Steering Group, and
sensitivity as well as high specificity because most of the others. Parents that agree to take part will be informed
relevant variants are known and can be sought. Disorders when a treatable early onset genetic disorder is identified
that are rarer will not have long lists of established patho- in their newborn.29 Treatment will be undertaken as part
genic variants and therefore the sensitivity of WGS for of routine care by the NHS. Genomics England will col-
these disorders will be much lower leading to more false lect data about the pregnancy as well as outcome data
negative results. from the child's NHS records over time. Additionally,
An additional consideration is the need to integrate these families will be contacted from time to time about
the current screening test results with genome sequenc- their child's health and their experience with the pro-
ing results. The current analyte testing must continue gram. Anonymized data will be made available to aca-
because molecular testing cannot replace screening for demic and pharmaceutical company researchers to
certain disorders. Many cases of congenital hypothyroid- discover new connections between genes and phenotypes
ism, for example, do not have an established molecular and to develop new treatments for genetic disorders.
basis and thus require analyte testing such as a TSH level An evaluation of the success of the program during
to find these children. It is likely that analyte testing and recruitment and after 100 000 cases are collected is essen-
genome sequencing will each find cases that the other tial. A work group has been established to identify the
technology misses. questions that should be asked, how the evaluation
A sample for genomic testing can be taken immedi- should be carried out, who will carry out the evaluation,
ately after birth as there is no need to wait for an abnor- and how the results will be communicated. There are
mal metabolite to build up in the infant over 1–2 days as three key elements to the evaluation. Do families see the
required by the current analyte screening. Genomics program as valuable and were they satisfied with the pro-
England is currently engaged in a pilot study to identify cess? Do pediatric specialists find that early identification
the best and most reliable source of DNA for its study. and treatment improves outcome in relation to the effort
The study is comparing dried blood spot on a standard involved in the program? Does the program make eco-
screening card, umbilical cord blood, and saliva from nomic sense?
newborns examining which sample type is obtained most Efforts to use genomic testing for newborn screening
reliably and which sample type yields the best, most con- are planned or underway in a number of centers world-
sistent sequence quality. wide, many of whom are sharing learnings and plans for
T A B L E 2 Unresolved issues in newborn genomic screening This question was explored in two contexts. First,
studies worldwide. the potential use of WGS as a technology in addition
Unresolved issues in genomic newborn screening to or to replace some parts of the current NHS new-
born screening program (which has defined purposes
How will genes and associated conditions be chosen?
and criteria) was discussed. Special focus was laid
How will we find enough screen positive cases for rare
upon the potential benefits and harms for the baby
disorders to give evidence for/against adding a gene to
newborn screening?
throughout their lifetime, for parents and the wider
family, for others in society, and for the NHS. Second,
Do we understand penetrance and expressivity of pathogenic
the potential novel or alternative uses of WGS in new-
and likely pathogenic variants found in an asymptomatic
newborn? borns – going beyond traditional screening and explor-
ing different purposes (e.g. lifetime monitoring,
Will we reanalyze the genome used for screening if a child
develops a phenotype suggesting a genetic disorder? pharmacogenomics, family planning, research, infor-
mation only) with respect to the potential benefits and
How long will families be followed to look for false negative
results and study outcome of screen positive results?
harms for the baby throughout their lifetime, for par-
ents and the wider family, and for others in society,
Will genetic disorders be included where there is not a
and for the NHS were explored.
treatment yet but a clinical trial available?
Participants took part in five online dialogue events
How will we ensure minority communities are well represented
with reflective tasks between each workshop in a dedi-
in the study?
cated online space. Each workshop was a mix of plenary
and break out discussions. The fieldwork took place
between February and March 2021 using public dialogue
example at the recent, inaugural International Confer- best practice in line with Sciencewise Guiding Princi-
ence on Newborn Sequencing.30 Each program will need ples.33 Participants reflected on the research question at
to navigate many scientific, medical, and ethical ques- each workshop drawing on expert presentations, case
tions. Unresolved issues in genomic newborn screening studies, and lived experience examples.
are listed in Table 2. Some issues such as the choice of Public dialogue is a qualitative methodology where
genes and conditions will likely yield different outcomes participants' views, concerns, hopes, and aspirations are
in different parts of the world according to the expecta- explored and presented. In Figure 1 it is shown, which
tions of parents in that country. The international new- people were involved in the dialogue process. The final
born screening community is just now starting on a report was published on July 8, 2021.34 The dialogue find-
journey to explore the risks and benefits of using geno- ings are now informing the development of a research
mics in newborn screening. The Genomics England pilot study, being run by Genomics England, for the Newborn
program along with others around the world will, hope- Genomes Programme23 on using WGS as a technology
fully, show that genomic testing can improve the lives of for newborn screening; discussions about the potential
newborns everywhere. for its use in population screening programs; and ongoing
public involvement in these activities.
The key findings on the use of WGS from the public
3 | A L IFET I ME 'S K N OWLE D G E dialogue in the report (Table 3) were that participants are
AT BIRTH? WHAT DO WE broadly supportive of the potential use of WGS for new-
ACTUALLY WANT TO KNOW? B Y born screening. However, they expect proper consider-
HENRIETTA HOPKINS ation to be given to designing and planning any future
use of this technology. This includes involving the public
A structured public dialogue to consider the implications in integration of the technology into any future research
of WGS for newborn screening was commissioned in or newborn screening and ensuring appropriate
September 2020 by Genomics England23 and the UK resources, investment and safeguards are in place to sup-
National Screening Committee (UKNSC) with support port and protect families and provide equitable access to
from UKRI's Sciencewise programme.31 It was designed potential benefits.
and delivered by the deliberative engagement specialists With respect to a future with WGS for newborn
Hopkins Van Mil.32 screening, participants felt that a future that included
The research question for the public dialogue was: WGS as a technology within newborn screening offered
What are the implications for the NHS and society of interlinked opportunities for society and the NHS. This
using whole genome sequencing (WGS) for newborn included delivering a seismic shift in current healthcare
screening? systems—moving toward a prevention-focused NHS. A
Speciﬁc perspecves groups:

People/Families with Genec
Condions
People with Black, Asian, and
Guided, challenged, and advised by the Minority Ethnic Backgrounds
Oversight Group and Project Team UK – a broad Young Adults
demographic New and Expectant Parents
17 11 ﬁlmed vox 29 speakers 7 pilot 84 public 49 public

stakeholder pop and dialogue dialogue dialogue
interviewees interviewees 23 observers parcipants parcipants parcipants
Geographic groups:
Scotland
Northern England
Wales and Northern Ireland
Southern England
FIGURE 1 The dialogue process involved the following people.34
TABLE 3 Key findings on the use of WGS from the public between certain ethnicities and genetic conditions
dialogue.34 could be made, potentially leading to discrimination or
It would be acceptable to use WGS to identify a wider set of stigma. In addition, there needs to be an assurance that
conditions than the current NHS newborn screening program the data will be held correctly and safely if they are
if: retained beyond the newborn period.
1 The conditions impact the infant in early childhood and In summary, participants are supportive of the poten-
2 There are treatments and interventions to cure, prevent, or tial use of WGS for newborn screening but only if proper
slow progression of the conditions. consideration is given to the design and planning of any
There is also potential for WGS in newborn screening to bring use of this technology; the public is involved; and appro-
health benefits to parents, siblings and the wider family. The priate resources, investment, and safeguards are in place.
following structures are required: The public engagement also acknowledged the
3 Genetic counseling and mental health assistance must be research value of the WGS data to deliver improved diag-
available for those who receive a confirmed diagnosis to noses, treatment, and care provided that the information
help them understand the health condition and to was anonymized.
provide emotional and psychological support.
3 A comprehensive genetic database should be established so
that people from ethnic minority backgrounds are not 4 | E T H I C S O F BI G D A T A A N D
disadvantaged by receiving more uncertain, or less WHOLE GENOME S CREENING:
accurate, diagnoses than the rest of the population from
HOW TO M AK E CHICKEN FROM
newborn screening—and the accuracy of diagnosis for
everyone is improved.
C H I C K E N SA LA D ? BY TA N J A
KRONES
4 The full complexities of WGS must be recognized when
designing consent processes including the implications of
WGS for the wider family and the child as it grows up. The often-uttered assumption is that main ethical ques-
tions and problems with regard to newborn genomics
5 If consent is sought for WGS data to be used for research:
the data must be anonymized and used to deliver
screening are primarily evoked by data security ques-
improved diagnoses, treatment, and care. tions. This is to prevent the exploitation of screened
individuals by insurances and employers, and the pro-
tection of the individual “right not to know,” while the
benefit of predictive genomics, also being described as
call was made for the benefits of WGS to be distributed the right to know, seems clear. These assumptions are
equitably across the United Kingdom with an inclusive paradigmatically expressed in a programmatic article on
approach to data collection and access to treatment. “P4 cancer medicine” followed by the so called “scien-
Participants see value in WGS data as a resource tific wellness study,” which can be linked to the current
throughout life, however, ethical concerns need to be whole exome sequencing (WES)/WGS newborn screen-
carefully considered. Concerns were that possible links ing programs.
4.1 | The “P4 revolution” TABLE 4 Findings in 120 healthy newborns undergoing
WES.45
In 2011, Hood and Friend published a programmatic arti- Findings in 120 healthy newborns undergoing WES
cle with the title “Predictive, personalized, preventive
11% “Unanticipated monogenetic disease risk” with
participatory (P4) cancer medicine,”35 in which they out- “pathogenic or likely pathogenic findings”
lined their vision of the future of medicine using individ-
88% One recessive carrier variant (considered as possibly
ual big “omics” longitudinal data and genetics as a novel relevant for future reproductive planning of the child's
preventive medicine approach. “Medicine,” they stated, parents)
“will move from a reactive to a proactive discipline over
5% “Atypical pharmacogenomic variants” that might have
the next decade. The ultimate promise is that the focus of an impact on medication taken in childhood
medicine will be shifted from disease to wellness and that
No evidence that parents have elevated psychological distress
billions of data points for each individual will define with during the course of the study
exquisite specificity the nature of wellness and any transi-
Preliminary evidence that the BabySeq approach is cost
tion into disease.”35 In this respect, they had the vision of effective, as it might prevent late-stage expensive diseases.
making personalized, data-driven, preventive coaching a
new wellness paradigm in the United States.36 Scientists
from the Department of Computational Medicine and
Bioinformatics of the University of Michigan followed Hood and Friend35 summarized that there are ethical
108 healthy individuals for 9 months, and collected challenges (will the accessibility of these anonymized
“personal, dense, dynamic data clouds” including data lead to exploitation by employers or insurance com-
genome-wide association studies for 127 traits and dis- panies), and security concerns (how will the data be pro-
eases, metabolomes, proteomes, microbiomes, and data tected) with predictive medicine. The same has been
from wearables at three time points during this period. discussed much more nuanced in the realm of the Baby-
Based on these data, actionable possibilities for behav- Seq trial, and even more in the current Genomics
ioral coaching were defined and three coaching sessions England approach including aspects of harm, justice, and
performed.37 However, what was actually provided were autonomy of the parents and the child.
visualizations of intercorrelations of the many variables
measured such as vitamin D, mercury, and HbA1c.
As nicely depicted by Berg et al.38 and Vona 39 it 4.2 | Ethical issues, theory of (natural)
was already in the 1990s that the possibility of science, and evidence-based medicine in
sequencing healthy newborns was foreseen by Nobel precision medicine: synergies and tensions
Prize winner Walter Gilbert. Among others, the in a nutshell
“BabySeq” project,40 which started in May 2015 as
part of the Newborn Sequencing In Genomic medicine To thoroughly assess the predictions and promises by
and public HealTh (NSIGHT) consortium41,42 has also some protagonists of the precision preventive genetics
targeted this some years ago. A total of 240 healthy and omics medicine approach, it is useful to investigate
newborns at the Brigham and Womens' Hospital and some fundamental questions with respect to the predic-
240 sick infants at the NICU of the Boston Children's tions and promises of “P4” medicine as listed in Table 5.
Hospital were included in a randomized controlled “Science,” as nicely stated by science fiction author
trial, performing WES in the intervention group. The Terry Pratchett47 “is not about building a body of known
study of healthy newborns is powered to test the facts. It is a method for asking awkward questions and
(non-inferiority) hypothesis that parents in the inter- subjecting them to a reality check, thus avoiding the
vention arm will not report greater distress plus human tendency to believe whatever makes us feel
greater utility in information received compared with good.”47 In other words of Mill48 and Popper49: Since
the control arm. more than 100 years we do not verify, but falsify hypothe-
Preliminary findings from the BabySeq project have ses, we do what fallible beings can do.48
been published,43–46 and revealed unanticipated mono- Medicine has always based its legitimization on basic
genic disease risks in 11% of newborn babies. Exactly 88% sciences, which have changed in the course of history—
of newborns had at least one recessive carrier variant that from magic (stone age) and pedagogic (ancient age) to
could be relevant to their parents' future reproductive the natural (laboratory) sciences and social sciences
planning, and 5% of babies had an atypical pharmacoge- (early enlightenment), epidemiology (20th), and the
nomic variant related to how they might process medica- “omics” medicine of today. All of these basic sciences—
tions used in childhood (Table 4). even magical effects (as can be seen in the best validated
T A B L E 5 Ethical questions with respect to the predictions and throughput technologies and computer sciences, includ-
promises of “P4.” ing machine learning and AI during the last two decades.
What is “good science” and what is “good ethics”? It is further believed that these associations/correlations
are directly clinically relevant and should change behav-
What are the goals of medicine?
ior and prescriptions. The scientific wellness study did
What is “system biology” and “P4 Medicine?”
exactly this and ignored even basic methodological
What are central questions and challenges posed by the “new requirements to assess effects from the epidemiological
revolutionary approaches” from the angle and perspective of
point of view. The study claimed to have shown a signifi-
natural sciences and evidence-based medicine?
cant effect via a complex intervention (measuring many
Which patients are targeted, who gains and who loses, when
data and applying behavioral coaching based on these
“P4 medicine” is implemented and prioritized?
data), thus, the PICO scheme should be applied
Which ethical principles are relevant and how are they (definition of population, intervention, controls, and
handled, specified, and weighed in “preventive genetic
patient-centered, clinically relevant outcomes). In
omics” medicine?
healthy individuals, with no underlying pathogenic
hypotheses, phenotype, or clinical question, a huge num-
ber of surrogate parameters was longitudinally measured.
effect in medicine, the placebo effect)—are still present There was no control group. If one measures parameters
in medicine which is not “applied human biology” but an in a cohort several times longitudinally, outliers will
art and action science, focusing on the usefulness in sin- always occur randomly and, if one focuses on these out-
gle cases and, due to its relation to health and illness, is liers, these will be closer to the average in the next mea-
inherently normative. Evidence based medicine, as surement. This phenomenon, already described by Sir
defined by David Sackett et al. in the programmatic arti- Francis Galton, is called “regression to the mean” effect,
cle in 1996 in the BMJ50 is “the conscientious, explicit, which might, explain the whole overall effect of the sci-
and judicious use of current best evidence in making entific wellness study.
decisions about the care of individual patients,” taking If the diagnosis in predictive genomic screening is
the critically evaluated external evidence, clinical experi- based on the existence of probable pathogenic gene vari-
ence, and patients values centrally into account. ants or genetic variants of unclear significance, without
Although epidemiology is not the only scientific base, it or only vague clinical evidence of a problem, there will
has become a very prominent tool to rigorously test be a system without negative feedback, which can be
hypotheses, to assess probabilities of prognosis, diagnosis, nicely explained by two sorts of “devil squares” of diag-
and causal effects with regard to therapy, using, for nostic testing in general as detailed in Tables 6 and 7 for
example, randomization and, if possible, concealment of devil squares screening and devil squares diagnosis,
allocation and double-blind trials to control for unknown respectively.52,53
variables, to minimize “the human tendency to believe The problem with these devil squares is, that
whatever makes us feel good”—and to avoid as much as although a primarily non-testing, a cautious wait-and-see
possible the causality-correlation confusion and induc- strategy with regard to medical action, as often applied in
tion problems already described by David Hume. The general practice with most symptoms disappearing with-
problems and false interpretations, if these methods are out treatment53,54 is of high importance to avoid overdi-
not applied, are summarized in the above-mentioned agnosis and overtreatment, the ascriptions of causality do
Wilson and Jungner WHO criteria4 considered still as a not foster defensive medicine, as testing and action seem
relevant methodological framework for screening also in better to categorize as many patients as possible in “devil
the genomic age.51 These are rooted in epidemiological square 1” for screening (Table 6) and to avoid “devil
knowledge and methodological rigor, leading to the square 4” in situations where symptoms occur. This is
assessment, that from a public health perspective, every the intuition patients have and many scientists and phy-
screening has to be thoroughly evaluated and its imple- sicians too.55,56 Yet, if not only screening healthy adults
mentation justified, as it produces false positive (and false becomes best practice but proactive preventive testing
negative) results, unnecessary medical procedures, and and treatment of all symptoms occurring in humans
physical and psychological harm.7 becomes the norm (devil squares diagnosis with symp-
Yet, “P4 Medicine” does not entirely rely on this line toms), we will not only end up in an overwhelmed, but
of thoughts—in fact, is primarily focusing on huge also ineffective and harmful defensive health care
amounts of data of single persons and aggregates, in system.53,56,57
“omics” mostly biological “big data,” looking for correla- The same might now happen in the BabySEQ trial.
tions by applying the technical tools, developed in high The first published case of the child with the diagnosis of
TABLE 6 Devil squares screening (based on References 52 predicted by the devil square logic described above. If, as
and 53). now suggested,46 every suspicious gene is considered
Disease(s) present Disease(s) absent
as possibly actionable and it is up to patients and parents
to decide if the genomic diagnosis is actionable, without
Active Devil Square 1 Devil Square 2
them having a chance to understand the problems of the
testing Reaction: Reaction:
“Gosh, so good we “false alarm”—relief “devil squares,” the risk of overdiagnosis and overtreat-
discovered the Side effects are ment becomes very high, even if there surely will be an
problem early” considered individual benefit for some children. If we take into con-
Side effects are justifiable as is sideration that the population screened are healthy new-
considered justifiable seems still better to borns and the primary results reveal that every 10th child
as the discovery of test than not to test is diagnosed with an unanticipated monogenetic disease
the disease always
risk and 88% as having one recessive carrier variant
seems more
(Table 4)45 what does the claim that every newborn
important, even if
there is no evidence should be screened in this way imply with regard to ade-
that this results in quate, cost-effective treatments and future care? What
lower morbidity or does it mean for future reproductive choices? From a
mortality public health perspective, will life expectancy of a popu-
No testing Devil Square 3 Devil Square 4 lation really increase if we focus on preventive measures
Reaction Reaction of unknown evidence in 10% of the population? Should
none, as the link “all good!” we offer carrier screening to almost every individual in
between no testing … although diseases the population? It is known that we almost all carry pos-
and a (future) might be present
sible pathogenic genes in our germlines, but as soon as
development of a
we have a clearly identified one, would we (or, are not
disease are often not
taken into we morally obliged to) refrain from spontaneous natural
consideration conceiving and always check our partners in a “gene
tinder”?
TABLE 7 Devil squares diagnosis (based on References 52

and 53). 4.3 | Excellent science and practice of
Good life/
medicine in the 21st century
disease course Bad life/ disease course
The ethical and scientific challenges of a thoughtful
Proactive Devil Square 1 Devil Square 2
treatment Causality Causality assumed: no WGS and WES, as prominently discussed by Nobel Prize
assumed: yes winners Syndey Brenner and Walter Gilbert during the
Physician as last years in many publications and interviews,58,59 but
savior also by Robert Green as one of the responsible scientists
Wait and Devil Square 3 Devil Square 4 in the BabySEQ trial60 is to make clear sense of the hay
see Causality Causality assumed: yes pile of data we measure and discuss advantages and dis-
assumed: no Physician might face advantages. It is easy to make chicken salad from a
malpractice suits chicken, but it is hard to make a chicken from chicken
salad:—to sequence the genome and measure millions
of targets via high throughput technologies without
good hypotheses how the genes work, to ignore induc-
partial biotinidase deficiency,43–45 shows a mother who is tion problems, conflate correlation with causalities and
very thankful as a problem was detected which can easily start trials without a deeper understanding of epidemio-
be treated by a vitamin only (Devil Square 1 in Screening logical phenomena and pitfalls is—in my view, neither
and Diagnosis). We do not know if the child will develop justifiable from a theory and practice of science nor an
a clinically relevant biotinidase deficiency, and the side ethics point of view.
effect that a child is medicalized as she has to take vita- What is good scientific and good ethical practice? In
mins regularly to prevent a clinically relevant course summary, it is decent, self-reflective, and challenging,
seems negligible. Parents are positive with regard to their asking for the state of knowledge while accepting that
trial participation. This is one of the main predefined out- there are blind spots, biases, and power plays in the
comes of the BabySeq trial. This could already have been realm of science. With regard to P4-, big data-, omics-,
TABLE 8 Big data informed consent checklist.66 5 | THE EURORDIS P ERSPECTIVE

Define WES/WGS and address its limitations
BY EDITH GROSS
Describe the processes and challenges of expert review that
Screen4Care is a 5-year long European Project, launched
determine the results to be returned
in 2021 and funded under the IMI2 (Innovative Medicine
Describe possible results related to diagnostic or incidental
Initiative). Its goal is to shorten the pathway to diagnosis
findings (if that distinction is appropriate for the context),
state the likelihood of producing such results, and indicate using advanced technologies, including newborn screen-
whether they are related to conditions that are preventable/ ing (NBS) and artificial intelligence applied to diagnosis
treatable of rare diseases.67 The NBS pillar of the project will create
Specify the meanings of positive, negative, and uncertain and learn from a pilot study to be conducted in Italy and
results Germany, where some 20 000 newborns will be screened
Describe the role of patient or participant preferences in return for either one or two panels (based on parental consent):
of results one for diseases defined as “treatable” (the “TREAT-
Specify the potential benefits and risks of participation Panel,” with around 80 conditions) and the other for dis-
(including benefit to society, when sequencing is performed eases where there is no known treatment or clinical
in the research context) interventions but are considered “actionable” (the “ACT-
Consider the many facets of privacy, placing findings in the Panel” with around 200 conditions) alongside the
medical record, de-identification, data-sharing, and risk of re- TREAT-panel conditions. While the criteria for the selec-
identification tion of the first set of diseases has already been defined,
we are now turning our attention to the second set of cri-
teria, with the concept of “actionability” requiring a
and AI informed-medicine, there are great achievements proper definition. The latter will be based on a literature
and pitfalls. Whereas these tools have the potential to review and empirical research including a questionnaire
improve the course of the disease in specific illnesses, survey to be held through the Rare Barometer Program
such as metabolic and oncological diseases, they are led by EURORDIS in the first semester of 2023, and sent
underdetermined with regard to theory of science, theory to almost 20 000 participants in the program, all people
of medicine, and ethics. Research in this field is mainly living with rare diseases and their family members. Since
in vitro/in silico making the measurable valuable instead Screen4Care is proposing a new approach to the diagno-
of the valuable measurable. In addition, there are high sis of disease, we are undertaking a conceptual and termi-
promises with regard to therapy, which may lead to ther- nological clarification process with a meaningful
apeutic misconceptions, with many treatments in rare empirical basis for the next steps in the definition of
diseases being highly expensive. Because of all of this, the “actionability” and in the decision making regarding the
central moment of good scientific critical reflection is panel to be proposed as part of the research project.
often not visible. In the course of 2022, we have conducted four group
A thoughtful approach builds on interdisciplinary sci- discussions with the EURORDIS Newborn Screening
entific knowledge, theory of science, context-sensitive Working Group (NBS-WG). The NBS-WG includes
ethics approaches,61,62 and evidence-based medicine.63 It patient representatives and experts from around Europe
is aware of the gray zones and uncertainties in science in the field of newborn screening. It has, among other
and medicine4,7,64 and the “devil squares of screening activities, formulated a milestone position paper on prin-
and diagnosis” as described above. It fosters real ciples of newborn screening.68 The consultations
informed consent and shared decision making via highly included open-ended discussions on the different aspects
skilled communications skills and the application of of newborn screening for actionable and treatable dis-
evidence-based decision aids (for newborn genomic eases, and an online survey using “mentimeter” where
screening65) that should include important information group members were questioned on their positions on
as the big data-informed consent checklist,23,62,66 as out- several vignettes, and several conditions in which to
lined in Table 8 and as included in the recommendations conduct NBS. The author also conducted one-on-one
of Genomics England. interviews with 12 stakeholders, including patient repre-
In conclusion, we should keep being enthusiastic sentatives, geneticists, and NBS policy experts, where
in research, but critical and decent towards our own were discussed ethical, technical, and social aspects of
and other results, beware of conflating research with actionability and addressed expectations and concerns
therapy, and choose wisely for and with our patients regarding the Screen4Care pilot and its meaning for pol-
while practicing the art of medicine also in the 21st icy. This was complemented by a review of the literature.
century. Screen4Care task members also follow our work and are
involved as the analysis develops. Another consortium, prospective or new parents, and the general public, show,
the Screen4Care Forum on NBS, will be formed in the overwhelmingly, that the preference would be for a more
first half of 2023 around the EURORDIS NBS-WG to dis- inclusive approach.78–82 Indeed, overall, the majority of
cuss the results and the application of the entire scheme people do want to have knowledge of conditions where
of genetic NBS (including the ACT, but also the TREAT there is a benefit beyond actual treatments, or in our
panel) throughout the last 42 months of the project words, where one can find Actionability in a broader
(up to October 2026). Starting March 2023, this Forum sense. Notably, in a review of 36 articles on the subject of
will meet for six workshops. It will include a core of genomic newborn screening, Downie et al.83 found a
members of the EURORDIS NBS-WG, as well as outside high level of interest (>60%), with a wide variation in the
experts and key stakeholders, for example, members of type of results to be returned: There was support for
learned societies, national NBS committee expanding NBS to include untreatable disorders,81,84 but
members, patient representatives, and industrials. less for genetic risk factors for diseases. Accuracy of the
At the point of writing this article, we are focused on test was deemed most important.85 Indeed, “parents
the launch of the EURORDIS Rare Barometer Survey believed they should be made aware of all results pertain-
on the subject of NBS, which outcomes will be applied to ing to their child's health status, and that they are respon-
further our work on the definition of actionability, to be sible for transmitting this information to their child,
used as part of the project and beyond. irrespective of disease severity. Despite potential negative
consequences, respondents generally perceived a favor-
able risk-benefit ratio in receiving all incidental
5.1 | Criteria for conditions for the findings.”86
Screen4Care project There are multiple benefits to be had with NBS. These
include the ability to prepare for a child's special educa-
As mentioned above, Screen4Care will propose two panels: tional and caring needs, but also be ready psychologi-
the TREAT-Panel and the ACT-Panel. The rationale behind cally, prepare for current or future detection and
this dual approach is that, while most current NBS pro- treatment opportunities, and informed family planning.
grams implement in their testing only conditions where What came up in studies is also the concept that knowing
there is a clear clinical benefit for the newborn, we want to is a benefit in and on itself, with the parents having the
consider as “actionable” conditions where other types of right to access all information on their children, and have
benefits can be identified (e.g., affecting reproductive a choice on what to know and not know. Another benefit
choices for the parents, ability to join a community, being would be avoiding a long diagnostic odyssey after symp-
prepared emotionally and technically). The position of the toms appear and providing parents with the opportunity
S4C consortium is that these benefits should be part of the to make informed decisions regarding medical manage-
discussion on newborn screening. Interviews and consulta- ment and educational interventions for their children, as
tions undertaken as part of the process leading to this paper well as the opportunity to participate in new and ongoing
confirm this necessity and highlight the need for a more research.79,80,82,83,87
holistic approach to risk–benefit analysis of NBS programs. Furthermore, if we look at knowledge as a necessary
The concept of actionability is already present in the benefit, one would be led to the conclusion that all dis-
literature,69–75 but we would like to explore it further by eases are “actionable” and should be tested. The concern
proposing a possibly broader meaning to the term. Tradi- would be to not provide information that is too uncertain
tional definitions of actionability refer to clinical actions (because then that would not be “knowledge”), but other
that can be taken based on the diagnosis.76,77 They than that, we have no restrictions on which information
include medical interventions (anywhere from curative to pass on. This stands in contrast to the “right not to
treatments to supplements, from diet to organ trans- know,” or “ignorance is bliss” or “golden years,” which
plants) and exclude actions that can be taken outside of are valid arguments. Yet, while knowledge can, according
the medical realm, such as a family's decision to move to to some, be a benefit in so many of the cases, one can also
another city for better access to care, or joining a commu- see the associated potential harms.
nity of carers dealing with the same or a similar rare dis-
ease. Indeed, within the traditional scheme of decision
making, the foremost inclusionary criteria for a condition 5.2 | The potential harms of NBS
in a newborn screening program would be the availabil-
ity of treatments. The literature clearly identified some of what could be
However, both our consultations and the literature on defined as potential harms to testing in some of the cases.
the attitudes of people living with rare diseases, Etchegary et al.,83 for instance, asked participants
whether or not there are conditions where newborn consenting process may be complicated and may require
screening should never be offered, and then analyzed the long consultations; Also, the management, access, and
open-ended comments justifying the answer. The themes storage of data can lead to significant ethical hazards;
that arose with respondents who felt there were some The broadening of the set of diseases being tested may
conditions whereas tests should never be offered were: lead more parents to opt-out of the testing altogether,
Misuses of the test for abortion/family planning and sex and may thus harm the current efforts. A consent process
selection; Characteristics of the test, such as it bringing where the test for some conditions is mandatory (or “opt-
questionably useless information, or it lacking accuracy; out”), while others are voluntary (or “opt-in”) may
Characteristics of the disease, such as its severity or per- address some of the issues.86
ceived seriousness, penetrance, age of onset; and socio-
cultural concerns, such as a potential for discrimination
and labeling of a child. In another study, Whitehead 5.3 | The frame of reference: Harm/
et al.87 identified the following themes with the critics of benefit to whom?
newborn screening in the absence of immediate treat-
ment, including, at the level of the individual child: dis- We have here defined relative harm and relative benefit.
rupting their identity development (their identification as But to whom do these apply? What is our frame of refer-
sick, overprotected, or “spoiled”) and the child's exposure ence? Obviously, considering solely the patient (or the
to unnecessary interventions. At the level of the family, baby), will result in a different calculation than if also
one may consider the creation of uncertainty and distress considering the family, or society.
due to false positives and a loss of carefree time before Clinicians adhere to a biomedical ethics code, which
the onset of the symptoms. At the societal level, one may focuses on the dyad of physician-patient and if the
think of the possibility of discrimination, the moral “patient” is the screened newborn, the frame of reference
blame that can come with having another child post- will remain this individual. This is also reflected in the
diagnosis and, more generally, a focus on NBS that may Wilson and Jungner's (1968) criteria,4 cited above. We
come at the expense of improving the diagnosis process. would like to see a broader frame of reference, which is
To those can be added the possibility that telling a patient usually used when discussing public health, where we
a condition can be “actionable” may lead them to think also take into account benefits of the family and society.
that more can be done that actually can,88 and the crea- Societal benefits include possible lowering of cost of treat-
tion of “patients-in-waiting” who would be subjected to ments and further R&D for conditions more likely to be
increased medical surveillance, potentially harmful inter- identified at birth, and thus bettering the condition of
ventions or useless tests. people living with rare and especially ultra-rare diseases.
However, the arguments of a “right not to know,” NBS can shorten the path to diagnosis, thereby lowering
and the right for the “golden years” where a parent and a healthcare system burden overall, not just economically,
child form a bond before the development of symptoms but also in terms of overall life gain or health gain for a
and the diagnosis, can be argued to be antithetical to the population.90,91
principle of autonomy, or self-determination, and can be Thus, this view extends beyond the traditional approach
seen as paternalistic. It can be relevant at the level of the of solely considering the benefits and harms to the individ-
person themselves, but it can be difficult to claim that it ual patient (here, the newborn)—such as avoiding unneces-
should be taken into account at the level of a general sary interventions and irreparable deterioration. It both
guidance for policy on medical knowledge sharing, broadens the views of harms and benefits for the infant,
whether genetic or otherwise. Some might say it can be and add concerns regarding the family and caregivers (for
harmful to others in some cases (such as for Huntington's instance, reproductive choices and psychological effects),
disease, where the diagnosis of a family member will lead and a wider consideration of societal goods (including
to questions regarding the diagnosis of others, who have opportunities for research and health-economics aspects,
not chosen to be tested or hold this information)—but both for rare diseases and for biomedical research and fund-
these are only extreme cases, and this argument itself ing/expenditure in general).
goes again the principle of autonomy for the individual The view on benefit can also not be solely seen on the
choosing to be tested.89 basis of a static state of affairs, it must take into account
Looking at the implementation of a program, one can future benefits of a decision, beyond the current existence
identify ethical concerns which are beyond the direct of treatment (such as research advances). For rare disease
potential harm of “knowing”: Potential harms can result advocates, the discussion might focus much more on the
from the inability of clinicians to interpret and effectively benefit to the family, and possibly on the benefit to
communicate genomics information on this scale; The research, taking a long-hold view of benefit—with most
cases not having proper treatment at the time of not tended to raise undue expectations or anxieties for
screening. families who simply treat this procedure as a routine pre-
Until now, most research has focused on a specific caution to identify a very limited number of rare condi-
condition, or has been conducted with the general public, tions, which if detected, will result in a tried and tested
that is, not with people living with a rare condition. This and effective treatment for their baby. Partly, as a result,
research will propose a wider definition of Actionability, it remains an acceptable intervention for families shortly
and, ultimately, on criteria for the inclusion of conditions after the birth of their child with uptake generally
in NBS based on a large number of responses from the exceeding 99%, a situation contrasting sharply with the
rare disease community, making this a unique opportu- poor uptake seen in vaccination programs in some
nity to gather insight and enrich our knowledge. regions and countries. We cannot afford to take this pub-
lic acceptance of newborn screening for granted.
The advent of first line genomic testing shortly after
6 | DISCUSSION birth considered by the presenters in this panel marks a
potential step change, not just in the technology used or
Whole population screening differs significantly from the range of disorders that may be included, but also in the
usual model of medicine where an individual seeks medi- implications for the wider family of this new “genetic
cal help to investigate, and hopefully successfully treat, a knowledge.” Perhaps most particularly it carries with it
symptom causing discomfort or distress affecting the per- an inherent public expectation that far outweighs that of
son themself or their child. Screening organized as part traditional screening with an embedded belief that, by
of a public health initiative alters this dynamic by offer- understanding the DNA of a newborn child, his or her
ing to investigate individuals or family members who life course may become clearer and future health risks
believe themselves to be well. The motivation underlying may be avoided. This is an onerous burden for policy
screening may also differ between the health profes- makers to fulfill and while current newborn screening
sional, seeking to identify and treat an individual before attracts little public awareness or attention, this form of
overt symptoms develop and the participant, who, partic- testing is liable to attract significant media coverage and
ularly for a new baby, may primarily be seeking re- raise huge expectations for some, and deep-seated fears
assurance that all is as well as it seems. in others, which could threaten the high level of public
It, therefore, comes as a great shock to new parents to acceptability that newborn screening currently enjoys.
be contacted to report that the newborn screening test In the series of talks on the topic of genomic newborn
has identified an abnormality requiring further action screening the speakers raised important key issues from
and raising the possibility of an unexpected serious or differing perspectives. David Bick described the ambitious
life-threatening condition in their child. The change from research plans of Genomics England to offer screening to
the symptom-driven model in medicine and the 100 000 newborns born in England based upon whole
undoubted stress resulting from this new situation of genome sequencing to identify a much wider set of condi-
genomic screening results with no biochemical or clinical tions than those currently included in the national screen-
correlates at that stage demands a great deal of thought ing program. The acceptability to embark upon this
and care on behalf of the system offering this form of research was based upon the findings of an extensive and
testing to ensure that the screening pathway and entry award winning31,32 public engagement exercise arranged
into clinical care, if required, is seamless, well organized in 2021. The report offered qualified public support by lim-
and family centered. Experience suggests that initial con- iting this to treatable disorders resulting in either cure or a
tact by a health professional forms an indelible memory slowing of the progression of disease in conditions that
in the parental experience and this event and the subse- would present in early childhood. It did acknowledge the
quent clinical investigation must be timely, scrupulously potential for health benefits for the wider family but
well organized, and offer clarity to parents who may stressed the importance of counseling and mental health
become very anxious as a result of this shock. support to deal with some of the issues that may be raised
These imperatives demand particular vigilance in the as a result of the testing. Bick suggested that 200–400 con-
operation of existing newborn screening programs and ditions might fulfill these conditions for inclusion. He also
immense care when any change or extension to screening pointed to the complementary roles of targeted genomic
is being considered. In particular, to maintain public con- screening and metabolite testing to correctly identify the
fidence, there needs to be a shared understanding about defined conditions in newborn screening.
what new forms of screening may offer, their limitations, Tanja Krones considered the ethical aspects of the use
and any benefits that they may confer upon willing par- of WES/WGS in newborn screening drawing upon propo-
ticipants or their children. So far newborn screening has sitions outlined by Hood and Friend in 201135 and
described as the “P4 revolution”: Predictive, Personalized, On that basis, Gross called for a re-appraisal of the
Preventative, and Participatory cancer medicine informed Wilson and Jungner (1968) criteria into a wider frame-
by “omics” captured longitudinal data including genetics work. Importantly she suggested that the Screen4Care
in order to define risks and to offer preventative interven- project will extend beyond looking to the benefits and
tions to improve health. Krones alerted listeners to the dif- harms to the individual patient identified by screening to
ficulty in establishing causality to outcome in such include benefits to family, caregivers, and wider societal
interventions and illustrated this with the “Devil Squares” benefits.
analogy in which a condition is identified by screening These interesting and topical contributions describe
and a good outcome is experienced even in circumstances newborn screening at a crossroads where new technology
where this may not have been a direct result of treatment. has the potential to provide new opportunities signifi-
A good current example may be the use of exon skipping cantly improving the quality of life for some or unleash
drugs to treat children with a designation of “cystic fibrosis new threats, which cast a long shadow over the growing
screen positive inconclusive diagnosis” (CFSPID). In these child and their family for others. These may be the loss of
patients, despite little evidence of effect, the maintenance autonomy of the child or implications on life or disability
of a disease-free state, in individuals who may have natu- insurance eligibility. The new technology has a signifi-
rally remained asymptomatic, is sometimes attributed to cant potential in the setting of clinical testing in symp-
the early identification of CFSPID and the treatment tomatic patients and offers great potential for research
offered. Conversely, when a physician adopts a “wait and but needs specific attention in the context of newborn
see” approach and an adverse disease course is experi- screening.
enced, the physician may expose themselves to criticism or In conclusion, it appears more important than ever
even potential litigation. This self-fulfilling prophecy of that as public, professionals, patients, and health policy
the benefits of screening, failing to take account of the makers we work together across national boundaries to
potentially unnecessary medicalization of the child and avoid, as TS Eliot92 might put it, “displacing wisdom by
family and yet laying claim to have secured a good out- knowledge and knowledge by information,” but rather
come, may be one of the most difficult and contentious of seek to make the most of new technologies while protect-
issues to address in screening and may prejudice or con- ing the sense of wonder and limitless potential that sur-
found a proper evaluation of the significance of risk factors rounds the birth of a new baby.
and their management identified following genomic
screening in early life. Krones concluded by advocating in AUTHOR CONTRIBUTIONS
favor of well-organized research in this area but stressed Each author wrote their own part and the different con-
the need for a critical appraisal of the results as this is contributions are clearly marked in the text. David Bick
sidered to become part of routine practice. wrote his part together with Richard Scott. Ute Spieker-
Edith Gross outlined the work of Screen4Care a koetter and James R. Bonham led the plenary discussion
European Project aimed at shortening the pathway to on genomic newborn screening at the SSIEM 2022 sym-
diagnosis for rare disorders by using artificial intelligence posium, provided a frame for the different perspectives
and genomic testing in a newborn screening context. and summarized the main discussion points in the manu-
Gross described the proposed use of two distinct panels, script. Ute Spiekerkoetter and James R. Bonham
one of which the TREAT-Panel predicted to include reviewed and edited the manuscript.
80 conditions where clear and effective treatments exist
that will benefit the baby identified. The second or ACT- ACKNOWLEDGMENT
Panel will include an additional 200 disorders where, Open Access funding enabled and organized by Pro-
while treatment for the condition in the traditional sense jekt DEAL.
may be lacking, early detection may offer other benefits
affecting reproductive choices for parents, time to prepare F U N D I N G IN F O R M A T I O N
the family emotionally and practically, and avoiding a No funding was received for this review.
protracted diagnostic odyssey before diagnosis is made.
Gross acknowledged the potential harms of newborn C O N F L I C T O F I N T E R E S T S T A TE M E N T
screening such as removal of the “right not to know” and US, JB, HH, DB, RS, and TK declare that they have no
bonding taking place during the “golden years” before conflict of interest. ESG is employed by Eurordis, which
the diagnosis of a serious illness in the child is made but is part of the Screen4Care initiative. Screen4Care has
suggested that denying that information could be viewed received funding from the Innovative Medicines Initia-
as paternalistic or an erosion of the right to self- tive 2 Joint Undertaking under grant agreement No
determination. 101034427.
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Received: 28 February 2023 Revised: 1 June 2023 Accepted: 13 June 2023

Genomic newborn screening: Are we entering a

Ute Spiekerkoetter 1 | David Bick 2 | Richard Scott 2 | Henrietta Hopkins 3 |

778 wileyonlinelibrary.com/journal/jimd J Inherit Metab Dis. 2023;46:778–795.

1 | INTRODUCTION of Muir Gray made in 2008 “All screening programmes

Speciﬁc perspecves groups:

17 11 ﬁlmed vox 29 speakers 7 pilot 84 public 49 public

FIGURE 1 The dialogue process involved the following people.34

TABLE 7 Devil squares diagnosis (based on References 52

TABLE 8 Big data informed consent checklist.66 5 | THE EURORDIS P ERSPECTIVE

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