GeneWatch UK response to the Human Genetics Commission’s Consultation on a
‘Common Framework of Principles for Direct-to-Consumer Genetic Testing
Services’
December 2009
GeneWatch UK welcomes the opportunity to respond to this consultation. Many of the
Principles provide important guidance. However, it is important to distinguish between a
system of oversight and regulation that is designed to facilitate the marketing of existing
tests, albeit with some additional information requirements, and one that is designed to
restrict the market in health-related tests to those that are genuinely valid and useful.
GeneWatch UK favours the latter approach, since we do not consider the provision of
reams of disputed technical information to be adequate to protect consumers from
misleading claims about their health, or to prevent the clear market failure that arises
when people have no means to independently assess or interpret such information for
themselves.1
In our view the proposed Guidelines lack legitimacy. A genuine consultation would have
been open to at least considering the option of gene test regulation and also included a
comparison with measures adopted in other countries.2 In proposing Principles which put
the onus on companies to declare their own compliance, the Commission has wrongly
sidelined the views of members of the public, including past exercises that have
highlighted public and professional support for the regulation of genetic tests: for
example, the 2003 Royal Society’s People’s Science Summit on Genetic Testing3,4,5;
and the Science Horizons project6,7. Instead, the HGC has chosen to develop Guidelines
in partnership with an international gene testing company (DeCode) which has
subsequently declared bankruptcy, and in the process has weakened its previous
(inadequate) commitment to at least some voluntary oversight via the MHRA (proposed
in Genes Direct). Further, the recommendations regarding clinical validity and utility of
tests appear to lack adequate understanding of both the science and health implications
of genetic susceptibility testing and the activities of the businesses involved. In
GeneWatch’s view, this is the wrong approach.
The international applicability of the Guidelines is also questionable, since no analysis
appears to have been undertaken of the potential role of ethics committees, data
protection legislation etc. in the global context in which genetic tests are now being
marketed (e.g. in China). Nor is there any discussion of the role of the FDA in genetic
testing oversight (the subject of a forthcoming US report) or the current process of
revision of the Medical Devices Directives in the EU.
The Principles are particularly inadequate in five important areas:
1. Failure to distinguish between reporting standards for genetic association studies
(e.g. the STREGA recommendations) and the validation of results, including
predictive algorithms. Positive predictive value and thus the validity of tests will
also depend on the population tested.
2. Failure to address the issue of clinical utility of tests, particularly their use to
recommend that some people will benefit more than others from
recommendations to change their lifestyle, such as quitting smoking or eating
particular diets.
1
3. Failure to recommend a system of independent oversight of assessments of
clinical validity and utility or any mechanism to ensure compliance.
4. Inadequate attention to the lack of public understanding of penetrance and the
harm that could be caused by misinterpretation of low-penetrance tests,
particularly in relation to feared diseases such as cancer or schizophrenia.
5. The lack of an adequate policing mechanism to prevent health-related tests
being performed on children and incompetent adults, in the absence of medical
benefit and without their consent.
We address each of these issues in turn below.
First we note that the ACCE process, which takes its name from the four components of
evaluation—analytic validity, clinical validity, clinical utility and associated ethical, legal
and social implications—is a widely supported model process for evaluating data on
emerging genetic tests.8,9 However, the Principles do not require any such assessment
process, nor do they put in place any mechanism to make such an assessment, nor do
they require any standards or criteria to be met.
The Council of Europe has adopted an Additional Protocol on Human Rights and
Biomedicine, Concerning Genetic Testing for Health Purposes10. The Protocol contains
provisions regarding non-discrimination, quality, information, counselling, consent and
privacy. Chapter III – Genetic Services – contains the articles of most relevance to the
Medical Devices Directives. Article 5 – Quality of genetic services – states:
“Parties shall take the necessary measures to ensure that genetic services are of
appropriate quality. In particular, they shall see to it that:
a. genetic tests meet generally accepted criteria of scientific validity and clinical
validity;
b. a quality assurance programme is implemented in each laboratory and that
laboratories are subject to regular monitoring;
c. persons providing genetic services have appropriate qualifications to enable them
to perform their role in accordance with professional obligations and standards.”
Article 6 – clinical utility – states:
“Clinical utility of a genetic test shall be an essential criterion for deciding to offer this test
to a person or a group of persons”.
It is surprising that the Principles do not refer to the ACCE framework or to the Protocol.
The provisions in the Protocol are consistent with the OECD guidelines, but go further in
that they require certain criteria to be met (not simply information published) before
genetic testing services are offered. The Principles undermine this Protocol because
they ignore these requirements in favour of allowing companies to sell anything they
want as long as they cite some relevant scientific literature.
1. Clinical validity
The only criteria cited in the Principles are that studies should meet the STREGA
guidelines (para 3.1). But these are reporting guidelines for association studies, not
validation requirements.
2
The HGC appears to be needed to be reminded of some basic science.
Most published gene associations are invalid and many false associations have been
repeatedly replicated in the literature before sufficient evidence has accumulated to
show the association is not valid. Thus, it is easy for companies to cherry pick the
literature and impossible to ascertain whether they are doing so without undertaking a
comprehensive search and analysis of hundreds, sometimes thousands, of scientific
papers. All the companies marketing gene tests based on invalid associations have
some literature which supports their claims: the process of assessment requires (as a
first step) an independent overview of these claims.11 The Principles provide no
requirement or mechanism for anyone to do this work.
Except for relatively familial forms of common diseases, where the genetic risk is
dominated by mutations in a single gene, most disease-related tests will be polygenic
and rely on algorithms that combine the risk of multiple genetic (and perhaps other)
factors. Companies often use an ‘additive’ model, based on the one originally written by
Ronald Fisher in 1918, although other algorithms have also been used. However, none
of these models have been validated for any complex disease, and there are an infinite
number of models that could be used to fit the data (i.e. calibrated to fit one or more data
sets).1 Different models will give different risk predictions, which will contradict each
other. Most (perhaps all) of these predictions will be wrong, or at best have limited
predictive value (as is normally the case for complex systems with multiple parameters,
e.g. the weather, hydrology). Unless there is a requirement for companies to validate
their models most of what is sold will continue to be rubbish (i.e. invalid), even if the
individual genetic variants included are genuinely associated with the claimed disease.
The positive predictive value, negative predictive value, sensitivity and specificity of the
tests will influence the balance of benefits and harms to the population tested. There are
no genetic tests for predisposition or susceptibility to common complex diseases that
currently meet screening criteria for the general population12 and many scientists are
sceptical that any ever will.13,14,15,16,17 Thus, all the tests currently on sale are likely to do
more harm than good. Because the Principles do not require any criteria to be met, they
will not change this situation.
It remains plausible that there will never be any genetic tests developed that are suitable
for use outside high risk families or people taking specific drugs. Even for a disease with
a high calculated heritability such as type I diabetes, there is currently a dispute as to
whether genetic susceptibility tests will not be useful at all18, or whether they will be
useful only for testing siblings of children who have developed type I diabetes at an early
stage.19 Currently, known genetic variants explain very little of the calculated
heritabilities of complex diseases.20 Calculated heritabilities provide, in any case, at best
an upper limit to the genetic component of the variance of any complex trait.21 Further, a
high heritability is a necessary but not sufficient condition for a test of high utility to
(potentially) exist once the relevant genetic variants have been identified.21
Overall, the lack of criteria in the Principles suggests that they are designed to endorse
the marketing of any associations that have been identified in published studies: this is a
very long way from establishing clinical validity.
3
2. Clinical utility
The US Secretary’s Advisory Committee on Genetics Health and Society (SACGHS)
defines the clinical utility for clinical decision-making as the balance between the benefits
and harms of testing and ensuing follow-up evaluation, treatment or prevention (page
117).22 Clinical utility must be evaluated within a specific context and utility may vary,
depending on the context and available alternatives.
In 2003, the Institute for Prospective Technological Studies (IPTS) of the EC Joint
Research Centre (JRC) warned that “the problem of increasing number of tests that are
performed with a dubious clinical utility should be considered as they might become in
the near future an unnecessary burden for health care systems” and
stated: “As there are potential harms attached to genetic testing, tests should only be
considered if benefits clearly outweigh harm”.23 The IPTS/JRC also noted: “There seems
to be a trend to overestimate clinical utility of the tests. It would be wise to set up a
European (or International) review board to determine whether the specific criteria have
been correctly fulfilled before a test is introduced in clinical practice or marketed as a
commercial product.” In 2004, the report of the EC’s expert group on genetic testing24
stated: “Proof of clinical utility and subsequent validation of all genetic tests are
prerequisites before their implementation into clinical routine”.
In its report of pharmacogenetics and pharmacogenomics (PGx), the IPTS/JRC has also
noted (page 19)25: “The In-Vitro Diagnostics (IVD) Directive sets out a common
regulatory process for diagnostic devices in the EU which include the test component of
a PGx drug-test combination. However, the EMEA is concerned that the CE mark is
granted solely on the basis of technical accuracy and not of clinical utility. This is
important as the evidence supporting clinical utility is regarded as one of the main
challenges facing PGx”.
By failing to include a requirement for tests to meet criteria for clinical utility in the
Priniciples, the HGC is in effect endorsing the sale of tests that have already had a
technology assessment that has concluded the test is of low clinical utility. As an
example, the US Agency for Healthcare Research and Quality (AHRQ) recently did a
technology assessment of outcomes of genetic testing in adults with a history of venous
thromboembolism (VTE) as part of the Evaluation of Genomic Applications in Practice
and Prevention (EGAPP) initiative.26 They conclude: “There is no direct evidence that
testing for these mutations leads to improved clinical outcomes in adults with a history of
VTE or their adult family members. The literature supports the conclusion that while
these assays have high analytic validity, the test results have variable clinical validity for
predicting VTE in these populations and have only weak clinical utility.”
Similar problems have plagued pharmacogenetic tests, which in general have also
shown low clinical utility,27,28,29 but some of which are nevertheless marketed as if such
technology assessments have never taken place30.
To understand why it is important to assess clinical utility it is also important to realise
that interventions should not in general be targeted at those at highest risk (as is often
claimed) but either at the general population, or at those who have most to gain from the
intervention. For risk factors which are amenable to intervention (such LDL cholesterol
levels), it is generally reasonable to assume that individuals at highest risk are the same
4
as those who have most to gain from interventions which lower the measured risk factor,
and to proceed with health advice on this basis provided this assumption is subject to
subsequent evaluation.
However, for fixed risk factors (where the intervention does not change the risk factor
itself) the risk-benefit ratio of an intervention may be lower, or no different, for an
intervention targeted at an individual in the high risk group, than for a member of the
general population. In other words, for a germline genetic test those who are at highest
genetic risk may not be those who have the most to gain (those who have the highest
risk-benefit ratio) from an intervention.31 This implies that zero or even negative health
benefit can arise from the process of using a genetic test to target lifestyle advice or
medication, compared to randomly selecting the same number of people from a
population, or compared to using another, better established (non-genetic) test. The
SACGHS report states: “The additional benefit or harm that would be achieved by using
the genetic test is called the incremental benefit or incremental harm. These benefits
and harms should be considered at the individual, family, and societal levels”.
For this reason, any assessment of the likely impact on health of genetic tests combined
with environmental or lifestyle advice requires knowledge of the magnitude (and sign) of
any gene-environment interaction.32,33 Such interactions are firmly established only for a
few common conditions, such as lactose and alcohol intolerance (although neither of
these conditions requires a genetic test for diagnosis). For diet-related disease,
marketing of genetic tests of questionable utility – because gene-diet interactions are
poorly understood - could have serious negative implications for public health by
confusing healthy-eating messages and undermining public health approaches.34
The situation is even worse for smoking. For example, criticism of the Respiragene
genetic test has (rightly) highlighted the lack of validation of this test to predict lung
cancer risk in smokers.35,36 However, its utility also depends on the claim (see graph in
the New York Times article37) that the genetic effect on risk does not occur in exsmokers/non-smokers (i.e. there is a gene-environment interaction, which leads to those
smokers at high genetic risk having more to gain from quitting smoking than others): this
is at best speculative, because this was not tested in the study.38,39 In practice, the low
calculated heritability of lung cancer (which is not in any case statistically significant)
renders the strong reported gradient in genetic risk of lung cancer unlikely and also
precludes the existence of a strong gene-environment interaction. Our (published)
calculations suggest that the highest possible utility for a lung cancer susceptibility test
could occur if 60% of cases occurred in 50% of smokers, rendering such a test
essentially useless, even if the validity of such a test had been established.21
Other, recently published, research we have undertaken – based on internal tobacco
industry documents, released as a result of litigation - has shown that the idea that a
genetic test could predict which smokers would get lung cancer was invented by
eugenicists working for the tobacco industry in the 1950s, and endorsed by leading
geneticists in the run up to the Human Genome Project, when they needed to
demonstrate the industrial applicability of the project in order to secure funding.40 This
(false) claim may have misled both smokers and policy makers, resulting in potentially
large numbers of deaths. The HGC’s approach to oversight of genetic testing might
benefit from a more critical assessment of such claims.
5
3. Independent oversight/regulation
GeneWatch has made a number of assessments of genetic tests marketed online and
via high street stores, pharmacies, medical professionals and alternative healthcare
providers. All the genetic testing companies we have criticised are adamant that their
test results are reliable and useful, although they all also criticise others as ‘cowboys’ in
the field. Often, companies appear genuinely ignorant of the literature or the limitations
of the data that they have. Thus, putting the onus on the companies to provide this
information is insufficient to ensure that it is not misleading.
For example, the Harley Street company Genetic Health provided us with 62 references
relating to the specific genes included in their tests, plus 42 (largely irrelevant) reviews.
Most of the references were out of date and had been superseded by more recent
studies, they also represented only a tiny fraction of the literature which we reviewed,
and ignored large studies and meta-analyses which should have been given the most
weight in establishing an association.41
The Oxfordshire-based company G-nostics eventually withdrew its (false) claim that its
Nicotest genetic test included a ‘nictotine addition gene’, but only long after the
newspaper headlines had proclaimed this to be true. The claimed association had been
invalidated in a meta-analysis and there remain serious scientific limitations to the
prediction of genetic susceptibility to nicotine addiction. 42,43 However, the company now
claims that it has new evidence that its programme ‘doubles’ quit rates (to 65% versus
35% at the NHS stop smoking service).44 This unpublished assessment is based on a
comparison after only 4 weeks of what the company calls a ‘pragmatic’ one-year clinical
evaluation.45 It is based on a self-selected population of smokers volunteering to take
part via its website. They are likely to be much more motivated to quit than the other
smokers in the study, biasing the findings.
The Google-backed company 23andMe’s scientific guidelines – particularly the
requirement that “sample size should exceed 1,000 cases and
1,000 controls”46 - are laughable in the context of the poor replication validity of genetic
association studies many times this size47, and the criticisms regarding the inadequate
statistical power of cohort studies such as UK Biobank (which aims to recruit 500,000
people) to quantify gene-environment interactions48. Other aspects of the guidelines,
such as the claim to focus on diseases fitting the “common disease, common variant”
paradigm are simply not followed: few diseases fit this paradigm, which is one of the
main reasons that genetic risk predictions are often contradictory.49
The problems with clinical validity and utility highlighted above apply to tests marketed
via private medical practice (such as Genetic Health), alternative healthcare providers
(such as the Genovations tests) and pharmacies (such as NicoTest), as well as via the
internet (e.g. 23andMe). This problem will inevitably impact negatively on the NHS, if
independent assessments of the clinical validity and utility of marketed tests are not
available to physicians in advance of products being sold.50 It is thus inadequate to
simply require companies to provide a list of published references – in our experience
many of these will have been invalidated or at best give a partial picture of the literature.
Since the HGC abdicated its own responsibility to ensure oversight of compliance with
the ACGT Code on the sale of genetic tests in 2001, no official body has done this job.
6
Has the HGC now abandoned its recommendation in Genes Direct that the MHRA
should do it? Even if the HGC sticks by this recommendation, it knows full well that the
MHRA opposes taking on this role and indeed has colluded with the industry, via the
Ministerial Medical Technologies Strategy Group (MMTSG) to oppose any assessment
of clinical validity or utility of tests. The MMTSG meeting papers from May 2008 include
a paper from the Association of British Healthcare Industries (ABHI) opposing attempts
to approve regulation of genetic tests and other medical devices at an EU level, via
revision of the Medical Devices Directives.51 In discussion, the industry’s position was
supported by the Medicines and Healthcare Regulatory Agency (MHRA).52 Does the
HGC agree, and, if so, why has it abandoned its commitment to transparency by failing
to inform members of the public how and why it came to this decision?
In GeneWatch’s view the recommendation in Genes Direct was already too weak,
because voluntary compliance will be impossible to achieve. But the current proposals
are a retrograde step in that they do not require even any voluntary oversight.
The adoption of weak Principles will, if anything, allow misleading marketing to increase
as companies will claim their tests are consistent with the Principles, when the HGC and
others (including their customers) will have no idea whether they are or not.
4. Low-penetrance v. high-penetrance and ‘lifestyle’ tests
It is appropriate to use a risk-based classification system, but it is not straightforward to
allocate genetic tests to risk categories prior to making an assessment of their clinical
validity and utility, in the context of the current limited understanding of the health
implications of most genetic variants (i.e. their novelty). This is because:
 Many so-called ‘lifestyle’ genetic tests contain genetic variants (polymorphisms) that
have been linked to serious conditions. For example, one company may sell a panel
of ‘cancer susceptibility’ genes, whilst another uses the same genes to predict ‘antioxidant capacity’ and recommend supplements.
 People taking genetic tests may not be aware that common genetic variants have
low predictive value and that one type of cancer gene test (e.g. of mutations in the
BRCA1/2 genes) has much more serious implications than another (of breast
cancer-related SNPs).
 A false distinction is often made between genetic disorders, such as Huntington’s
Disease, and complex disorders, such as Alzheimer’s Disease, schizophrenia or
cancer, in relation to their seriousness or the potential risk associated with genetic
testing. Although tests for genetic susceptibility to the latter are much less predictive,
they are equally feared diseases and the consequences of false positive and
negative results may be equally harmful, as well as more likely to occur.
 For less-feared conditions such as obesity and other diet-related diseases, the public
health consequences of widespread misleading genetic information may be very
serious, even if the impact of such misinformation on individuals may appear to be
relatively trivial.
 Genes linked with one condition may be linked later with another, with potentially
very different implications (such as the link between APOE genetic variants and risk
of Alzheimer’s Disease).
The number of tests currently sold in the UK is likely to be small, but GeneWatch has
been contacted by people overseas who have highlighted the difficulties that members
7
of the public have in understanding what is being sold to them. In one case, the husband
of a woman who had taken a misleading (invalid) panel of breast cancer SNPs explained
how she had thought these gave equivalent information to the BRCA1/2 ‘breast cancer
genes’ and gone on to take unnecessary additional tests (the company involved has
since added a disclaimer to their website, and removed the list of SNPs included in the
test). In another case, the father of a child expressed concerns about a gene test based
on a panel of SNPs claimed to be related to autism (again invalid) which his wife had
obtained for their son via an alternative healthcare provider. Amid numerous press
reports of ‘autism genes’ and ‘breast cancer genes’ it is unreasonable to expect
members of the public to be aware that what they are buying has no predictive value.
Some Commission members will remember that the concept of ‘lifestyle’ tests was
invented by Sciona (the UK company that marketed genetic tests with dietary advice in
the Body Shop in 2001, subsequently moved to the USA and has now gone out of
business) in order to avoid scrutiny by the HGC under the former ACGT Code, and
potential regulation under the IVD Directive. After its relocation to the USA, the US
Government Accountability Office reiterated many of the concerns originally raised by
GeneWatch UK and the Consumers’ Association about Sciona’s tests.53 It is therefore
surprising to see tests combined with lifestyle/environmental advice, or claiming to
predict behaviours, being treated as if they are not health-related in the HGC’s proposed
classification scheme.
Concerns will grow significantly if the market expands and if gene test providers press
ahead with susceptibility tests for complex conditions such as schizophrenia (likely to be
used on teenagers with relatives with the condition). Although the concept of a single
‘predisposition’ gene for schizophrenia has been proven to be false, this was long
promoted by geneticists as the most likely explanation for this condition. It would
therefore not be surprising if many families still believe this to be the case: the
consequences for young people with relatives with this condition if they are given
misleading genetic information, could be very serious (including, in a worst case
scenario, potential suicide).
Leading UK psychiatrists have previously denounced plans by US companies to market
genetic tests claiming to identify susceptibility to bipolar disorder (manic depression) or
schizophrenia on the internet.54,55 To date, Neuromark and SureGene appear to have
delayed marketing such tests, but Psynomics is already selling a test claimed to be
linked to biopolar disorder. 23andMe provides a ‘research report’ on disease risk for
schizophrenia, based on an association with a single gene (GNB1L) in a single casecontrol study (including 803 men with schizophrenia or closely related disorders and
2,025 healthy men).56 Three recently published studies identified 30,000 genetic variants
that may be linked with schizophrenia (although most were not individually significant).
57,58,59
The discoveries may provide new clues to understanding the condition: for
example, many of the genes are linked to the immune system, perhaps suggesting that
a virus might play a role. However, each gene increases the risk by only about 1% and
scientists do not know how these tiny differences in individual risk might be combined to
attempt to predict who might develop schizophrenia. One of the authors of the studies
warned that: "It would be unscrupulous for anyone to use these data for genetic testing
for schizophrenia".60
It is surprising that the HGC appears to regard marketing of such tests with equanimity.
One danger of the HGC’s proposed approach is that, by allowing companies to state that
8
they have endorsed the Principles without any mechanism for oversight of their claims,
potential customers are actually encouraged to believe in the reliability of tests that they
might otherwise have treated with more wariness.
For these reasons, all health-related genetic tests (including so-called ‘lifestyle’ or
behavioural tests, and pharmacogenetic tests) should undergo a full pre-market
assessment of analytical and clinical validity and clinical utility, overseen by an
independent regulator. However, subsequent requirements (such as the level of medical
involvement and counselling required) might then be very different depending on the
test.
5. Children and incompetent adults
GeneWatch welcomes the HGC’s decision to support the view that companies should
abide by established ethical standards and not test children on the basis of parental
consent unless this is strictly necessary for their medical care. Our understanding is that
the law in England and Wales is that children who are under 16 are considered to lack
the capacity to give their own consent to testing and that it may be unlawful in any case
for parents to override this except in cases of medical necessity. Rather than seek to
devise a complicated (and probably unreliable) process to ensure this requirement is
met online, the need to meet this important standard suggests that tests should only be
offered via medical professionals, so that samples are always collected face-to-face
(regardless of counselling requirements). This would bring the Principles in line with the
best interests of the child, rather than being driven by the online marketing plans of a
small number of companies, and ensure compliance with the law. It would also help
prevent the illegal testing of incompetent adults.
Conclusion
Rather than adopt weak Principles with no mechanism for oversight, the HGC should
recommend that the Government signs and ratifies the European Convention on Human
Rights and Biomedicine, and its Protocols, including the Protocol Concerning Genetic
Testing for Health Purposes. If it wishes to overturn the principles adopted in the
Protocol, perhaps the Commission could explain why it considers why a ‘right to know’
invented by commercial companies (actually a right to be sold misleading rubbish by
such companies) should take precedence over the rights adopted in this international
instrument.
The Commission should also support attempts to make the EU’s Medical Devices
Directive consistent with the Protocol, during the current process of revision.61,62
For further information contact:
Dr Helen Wallace, Director
GeneWatch UK
60 Lightwood Rd
Buxton
SK17 7BB
Tel: 01298-24300
Email: helen.wallace@genewatch.org
Website: www.genewatch.org
9
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