The progress of molecular genetics

GREAT SCIENCE is characterised by discovery and by finding solutions to real problems. Unlike physics, where a prediction based in theory leads to a search for supporting evidence, progress in biology depends more on systematic experimentation and observation than on any grand hypothesis. This is because biological systems have sequentially and adaptively evolved via mutations in the designer code of our genes. Without an overarching theory, researchers are required to tease out the molecular details of how life works.

Crick and Watson’s seminal model for DNA structure has led to the new field of molecular genetics. Still in its infancy, the discipline has been moving from the research laboratories to applications that inform medical practice.

Those of us active in clinical practice, though familiar with the basic pathway from DNA to protein, are likely to have a limited understanding of molecular genetics, depending on our graduation vintage and our ability to keep up with the field. That is why it is worth spending a little time and money on award-winning science journalist Elizabeth Finkel’s new book.

It is intended for a lay audience; however, though still active in immunological research, I had many knowledge gaps filled by its easy style and personalised accounts.

What is your understanding of terms like genomics, histones, epigenetics, RNA interference? Is much of the genome still assumed to be comprised of useless “junk”? Not so, it seems, and Finkel tells us why. How useful is investigating the genetic basis of various cancers, and what progress has been made with the substantial research funding involved? We all know about BRCA1 and BRCA2 genes in breast cancer and test for them in practice, but what about genes possibly implicated in colon cancer? How has the idea of a genomically based “personalised” medicine evolved? Finkel tells us that there is a way to go, but the field is moving forwards.

The book covers a little of the early history and then moves on to explaining disease processes with an obvious basis in molecular genetics. Discussion is then broadened to how the DNA revolution might contribute to sustaining a probable 9 billion people on an increasingly environmentally challenged planet. Anyone who talks regularly with the public can benefit from this discussion, where there is an increasing focus on the supposed dangers of genetically modified foods. The book ends by inviting you to “Meet your ancestor”, retracing the long story of evolution of ourselves and other extant life forms.

The genome generation is thus a clear and accessible overview as well as a ready reference. From the era of great men and grand theories, biological science has moved on to a time when the latest experiment or datasets lead astute minds to consider every possibility. Finkel’s book gives a good understanding of how we are “instructed by nature” in the world of molecular genetics.

Challenges of transition to adult health services for patients with rare diseases

What can be done for young people stuck in “health care limbo” when they leave paediatric services?

The teenage years are a time of transition, when young people must adapt to enormous physiological and emotional changes but also need time to aspire to the future. Young people living with chronic complex disease have dreams, but their challenges are amplified as they face transition from paediatric to adult health services and begin to take charge of their own complex health care needs.1

Young people need the assistance of adult health services to deal with adult issues: sexual health, fertility, drug and alcohol use, mental health, lifestyle-related disease and issues related to disability, employment, education and training. For most of their lives, young people with chronic diseases have been engaged in a paediatric, family-centred multidisciplinary model of care. They need preparation and support to move into adult services, which are more specialised, less integrated, and centred more on the individual than on the family.1,2 Failed transition leads to poor engagement with health services and adverse health outcomes.2

Despite a number of policy initiatives to provide age-appropriate and stage-appropriate care for adolescents and the development of disease-specific transition pathways (eg, for cystic fibrosis, spina bifida and diabetes),1,3–5 transition is fraught for young people living with chronic and complex diseases, especially rare diseases.

Providing disease-specific clinics for every rare disease is unrealistic; there are almost 10 000 rare genetic diseases alone. Most rare diseases have their onset in childhood, are chronic, complex, disabling and require frequent, specialist care throughout the life span.6 This necessitates access to multiple doctors, allied health workers, pathology and pharmacy services.7 Better recognition of rare diseases and increasing survival rates have led to a greater demand for transition services from this group and we must respond to their needs.

Regardless of which chronic and complex disease they have, these young people face similar problems with the transition to adult care:

inadequate preparation
difficulty finding appropriate adult health services
inadequately coordinated specialist adult services
unwillingness of general practitioners to take on complex cases
inadequate resources to coordinate the transition process
lack of psychological support.

These issues were affirmed in the recent Forum for Young People Living with Rare Disease, attended by 15 young people and 15 parents or carers representing a wide variety of rare chronic conditions: Ehlers–Danlos syndrome, Klippel–Trenaunay syndrome, narcolepsy, cataplexy, Phelan–McDermid syndrome, Duchenne muscular dystrophy, Rasmussen’s encephalitis, congenital panhypopituitarism, hypochondroplasia and other skeletal dysplasias.8

Forum participants called for:

comprehensive preparation for transition, involving the family and adult services
timing of transition according to developmental stage and maturity, not age
flexibility from adult specialists to allow parents and carers to attend some consultations
clinics that treat many different rare chronic conditions
GP clinics that are competent and confident to coordinate care and refer appropriately
accessible transition coaches or coordinators.

One 18-year-old with a rare syndrome said:

I’m still transitioning, but it’s been a trial. I’m too old for paediatrics but too difficult a case for adult services to treat. I am worried about my health . . . I don’t know who will treat me properly if I end up in hospital.

As most rare chronic diseases are initially diagnosed and treated in childhood, much of the expertise resides with paediatricians, and often there is simply nowhere to transition to. We need to address this imbalance by supporting education on chronic complex diseases in young people — both for medical students and through continued medical education. The ongoing development of the specialty of Adolescent Medicine will support this.

Multidisciplinary clinic models catering for young adults could be adapted to cater simultaneously for many different rare diseases.5 Such innovative models provide economic efficiencies,9 facilitate communication among the many health professionals involved in care and ease access for patients. Establishing clinics that involve both adult and paediatric specialists enables sharing of expertise and provides a practical training platform. Incentives beyond the current Medicare rebates are needed to support specialist GP clinics willing to look after young people with rare chronic diseases. Trapeze, a primary health transition service, has been established in New South Wales, although its current focus is limited to diabetes and respiratory disease.10

Young people living with rare chronic disease have the right to equitable access to appropriate health care. We need a network of appropriately trained and well resourced transition coordinators to facilitate linkages between young people and health and psychological services and peer support.8 Evaluation of existing transition services and clinics to inform future service needs should be a priority. Successful transition requires more than a referral letter. It is a process that takes time and requires a coordinated system-based approach.

Direct-to-consumer genetic testing — clinical considerations

Do-it-yourself mail-order tests — how should a doctor deal with them?

Health-related direct-to-consumer (DTC) genetic testing enables consumers to test for changes in their genome that may assist with diagnosis or screening for particular disorders or traits, and may help predict future disease or response to treatments. DTC testing allows this to be under the consumer’s control and, at least initially, does not involve a medical practitioner in ordering or interpreting the test. However, this control is traded off against uncertainty about how clinically relevant the tests or their results are for consumers and their families. There are important ethical and legal considerations, particularly if these tests are ordered from overseas laboratories. Consequently, for medical practitioners, DTC testing poses the problem of how it can be assimilated into practice.

The DTC genetic testing landscape

A 2003 report by the Australian Law Reform Commission predicted that the number of DTC testing laboratories would grow from the small number operating at the time.1 By 2010, there were over 30 DTC companies, mostly in the United States, whose services were made viable by the robustness of DNA samples sent in the mail, and the growing numbers of available human genetic tests.

The landscape of DTC genetic testing companies is now more complex. Today, there are fewer genetic testing laboratories classified as DTC (about 20) because some companies advertise their DTC tests through the internet, but require a medical practitioner to order them.2 These are not true DTC testing facilities, although they pose some concerns, as will be noted later. It is also important to distinguish DTC genetic tests offered through providers in Australia from those offered by overseas companies, with consequences for regulation and consumer protection.

Rationale and product for sale

Advocates for DTC genetic testing argue that it allows individuals to manage their health more proactively. No one would disagree with this goal. The problem is how DTC tests are advertised and delivered. Opponents of the DTC approach highlight the risks of unproven products being marketed as providing information on clinically significant genetic disorders or traits, where consumers may not be assisted by professionals in assessing the suitability, accuracy or significance of the genetic tests.

Another attraction for consumers of DTC testing, particularly when it is available over the internet, is convenience and greater autonomy in the health system. Traditional genetic testing services provided in Australia are predominantly delivered through public hospitals and can be difficult to access, and they may not be funded through Medicare. In accessing these established services, patients take on a traditional submissive role, which is increasingly at odds with moves toward a doctor–patient collaborative model of care.

DTC genetic testing companies advertise tests for a number of health-related disorders. Sometimes, they provide consumer information about the evidence underpinning the test. For example, one company distinguishes tests based on established research reports, considered to contain reliable findings, or preliminary research reports, considered by the scientific community as needing confirmation.3

Associating a genetic test with medical research gives it some legitimacy but does not indicate whether it can be successfully translated into use in a clinical setting. A term such as “reliable” used by the company to describe the findings of established research reports is imprecise when determining the clinical value of the test. It is even more difficult to see any justification for the use of preliminary research reports in advancing patient care (Box 1).

In response to criticism, companies have relabelled their DTC genetic testing products as “information” rather than as tests for clinical decision making, using various disclaimers. In its sample result for a genetic predisposition DNA testing report, an Australian DTC company (certified to the standard ISO 17025 — see below) states:

This report is provided to you for informational and educational purposes, and it does not replace a visit to a physician, nor does it replace the advice or services of a physician.4

Issues for medical practitioners and consumers

Analytic validity

Analytic validity refers to whether a test accurately shows what it is purported to show in terms of DNA-based information. For Australian laboratories, accreditation (non-compulsory unless the test is funded by Medicare) through NATA (National Association of Testing Authorities) provides a means of evaluating this. There are two relevant standards: ISO 17025, which is generally used for a range of laboratories or testing facilities, and a higher standard ISO 15189, which is required for medical testing. So, a medical practitioner (and the consumer, if aware of the relevant standards) could check a laboratory’s accreditation. If a DTC genetic testing laboratory is selling only “information”, it might argue that the lower of the two standards is sufficient. It is more difficult to assess accreditation in overseas companies because requirements differ between jurisdictions. The results of a study on analytic validity for DTC genetic testing were published in 2009 (Box 2).5

Clinical utility

This measure is important for all genetic tests — will the result lead to any meaningful changes in medical management? To consider this it is necessary to review the types of human genetic disorders for which genetic testing is possible.

Mendelian type disorders: Cystic fibrosis (CF) is a single-gene autosomal recessive disorder. A symptomatic newborn child can be confirmed to have CF if he or she is homozygous for the p.Phe508del mutation, the most common one associated with CF. Based on this result, appropriate therapy for CF can be instituted. Therefore this test is clinically useful. Testing for Mendelian disorders is available through conventional genetic testing services in Australia and DTC services.6 Thus, the same genetic test can be provided either in the controlled context of medical advice, or through a DTC mechanism which takes no responsibility for its use in medical decision making. One should also note that not all Mendelian-type genetic tests will have clinical utility. For example, the same CF test sought in a healthy young adult with chronic lung infection will be meaningless because the individual is unlikely to have CF. Even if the individual had, in theory, an extremely mild form of CF, it will not be detected because the range of mutations sought in genetic testing are for severe forms of CF.

Complex genetic disorders: Forty or more genes or genetic loci are implicated in type 2 diabetes. These genes have been identified through population research studies. Tests for complex genetic disorders are not provided by the traditional genetic testing laboratories but can be obtained through DTC laboratories. The problem is whether results from population studies can be translated directly into risks for individuals, without accounting for ethnicity, as many research studies are based on Caucasian subjects. Even if the relative role of the genetic component in disease was precisely understood, we know that environmental contributors to pathogenesis are important. For these reasons, there is very little to no evidence at the moment that genetic testing for complex genetic disorders has any clinical utility.

Support and counselling

Genetic counselling (often absent from DTC tests) is a key component of clinician-mediated genetic testing, particularly when the test result and its implications are not straightforward for the individual and his or her family members. Some DTC laboratories now provide access to user-pays phone and online counselling services, but their standards are difficult to evaluate. They may be located overseas and so the consumer has minimal legal protection if advice is incorrect.

Some DTC genetic testing scenarios for the medical practitioner

Request for testing

The medical practitioner might be asked to order a test because the patient or the patient’s friends or family members are prompted to request one by word-of-mouth or internet advertising. The doctor should consider the analytic validity and clinical utility of the test. A doctor who is in doubt might still order the test because the patient has made the request, the patient will pay for it and, in Australia, there is little formal guidance on clinical utility. But inevitably, result interpretation will be required. This scenario is likely to lead to incorrect diagnoses, leading to more referrals to specialists and a growing cohort of “worried-well” patients.

Some emerging publications have highlighted the impact of DTC genetic testing on consumers’ health, particularly the risk of anxiety. One recent study came to the conclusion that there were no untoward psychological effects or unnecessary screening tests ordered.7 However, some final comments in this report noted important limitations, making the conclusions tentative.

Request for advice

A patient may present with the results of DTC genetic testing and seek assistance in interpreting them. An example might be a 10-fold increased absolute risk of developing type 2 diabetes. What does this mean in a context where environmental factors are very important in pathogenesis? This small change in risk (assuming it is correct) is presently less helpful than clinical assessment for obesity. Since the medical practitioner did not order the test, he or she is unlikely to have much understanding of its clinical utility, and very few genetic markers for complex disorders have been evaluated for this. In addition, DTC testing laboratories offer panels of tests for different genetic markers, so results are likely to be presented as a list of risks (high, low or population-level) for many diseases.

When dealing with a serious disease such as cancer, the medical practitioner might need to consider implications for family members. However, in a recent Australian survey on the impact of DTC genetic testing on health professionals, it was noted that only about 7% of genetic specialists were confident in interpreting DTC genetic test results.8 If these specialists are having problems, then non-specialists will be immensely challenged.

Oversight

Regulatory bodies initially did not consider DTC genetic testing as it was relatively low profile. The DTC industry achieved some notoriety following two enquiries by the US Government Accountability Office, which showed fraudulent practices by some DTC companies.9,10 The United Kingdom’s Human Genetics Commission (HGC) has published recommendations on standards to promote self-regulation, as have the Human Genetics Society of Australasia and the National Health and Medical Research Council of Australia through the production of guidance and information documents. However, the HGC document was criticised because recommendations alone are unlikely to change behaviour without some oversight or incentive to comply.11

A separate regulatory issue is truth-in-advertising. Presumably, DTC companies have received legal advice that selling a product as “information” rather than a medical test is the appropriate way forward. Nevertheless, some websites appear to imply a link between genetic testing, “information” and health outcomes, so the issue of potentially misleading advertising may need to be revisited.

Future

DTC genetic testing will continue to evolve. Linking company services with the requirement for medical practitioners to order the tests is a step in the right direction, but only if medical practitioners have the confidence and eHealth-based tools to determine what tests are clinically relevant and the significance of results. For this it will also be necessary to know about a test’s analytic validity and clinical utility.

1 Selected genetic tests out of the 247 direct-to-consumer tests offered by one United States-based company3*

Test purpose
(no. of tests offered)

Examples of available tests

Comments

Carrier status (49)

Cystic fibrosis†

Haemochromatosis†‡

Sickle cell anaemia and malaria resistance†

Tay–Sachs disease†

Relatively straightforward genetic tests dealing with Mendelian genetic disorders and seeking mutations that interfere with gene function. The results should be interpretable, although professional input may be needed. Most of the tests are likely to have clinical utility. Subtle details of the claims made on the website may be misleading, eg, the linking of sickle cell anaemia with malaria resistance on the company’s website is correct from an evolutionary sense but misleading if it suggests that an individual with sickle cell anaemia is resistant to malaria.

Drug response (21)

Abacavir hypersensitivity†‡

Heroin addiction¶

Naltrexone treatment response¶

Alcohol consumption, smoking and risk of oesophageal cancer†

Testing for the appropriate human leukocyte antigen type before treating with abacavir can reduce the risk of the potentially fatal Stevens–Johnson syndrome. This is an example of how genetic testing can inform treatment options. In contrast, it is not clear how performing the other three tests would lead to changes in drug response or behaviours. Further, these tests are based on preliminary research reports. It is uncertain how the results are interpreted for individual customers.

Disease risk (120)

Asthma¶

Bipolar disorder†

Creutzfeldt–Jakob disease¶

Gout¶

Hypertension¶

Obesity†

Diabetes (type 1 and 2)†

Testicular cancer¶

The examples given are only a few of the 120 tests that are identified as assessing disease risk, yet the clinical utility of most genetic tests remains to be demonstrated (even for bipolar disorder, which in this list is considered based on an established research report). They all provide “information”, but it remains to be proven whether it is sufficient or even correct to alter lifestyles based on this information, and whether there will be an impact on outcomes. Many of the tests are for complex genetic disorders, where the relative contributions of genes and the environment are still to be determined.

Traits (57)

Birth weight¶

Height¶

Smoking behaviour†

Blood glucose¶

Breastfeeding and IQ¶

Eating behaviour¶

The same comments apply here as for the disease risk category, although it would seem even less likely that a genetic test will provide relevant or useful “information” about these traits.

*The disclaimer after the list of genetic tests offered by this company reads: “The tests have not been cleared or approved by the FDA [Food and Drug Administration] but have been analytically validated according to CLIA [Clinical Laboratory Improvement Amendments] standards. The information on this page is intended for research and educational purposes only, and is not for diagnostic use.” † Tests considered to be based on established research reports. ‡ Funded through Medicare. ¶ Tests that are considered to be based on preliminary research reports.

2 Results of a study assessing the performance of two direct-to-consumer (DTC) genetic testing laboratories5

A 2009 study compared the results from two leading United States-based DTC testing facilities that had been sent the same five DNA samples. The results showed an excellent (99.7%) agreement for genetic markers that could be compared. To some extent this would be expected, as most genetic testing laboratories now use sophisticated and automated analytic platforms that reduce the margin for (non-human) error. Thus analytic validity should not be a significant problem in a competent DTC laboratory. In contrast, the study showed disturbing differences in the clinical interpretation of results provided for the same disease and testing the same sample. These inconsistencies included receiving a “high risk” from one laboratory and a “low risk” from the other for prostate cancer, type 2 diabetes, psoriasis and Crohn’s disease.

This example illustrates the importance of distinguishing two aspects of a genetic test: analytic validity and result interpretation. Result interpretation is increasingly becoming the limitation, as the data generated need to be interpreted in terms of biological significance (ie, is this a true DNA mutation leading to a change in gene function?) and clinical significance (ie, what does the genetic test result mean for a patient and his or her family in terms of clinical care?). Hence describing a genetic test with a vague term such as “reliable” is ambiguous as it is not clear whether this refers to the analytic validity or the result interpretation, or ultimately, the impact on patient care.

Direct-to-consumer genetic testing — where should we focus the policy debate?

What are the implications for health systems, children and informed public debate?

Until recently, human genetic tests were usually performed in clinical genetics centres. In this context, tests are provided under specific protocols that often include medical supervision, counselling and quality assurance schemes that assess the value of the genetic testing services. Direct-to-consumer (DTC) genetic testing companies operate outside such schemes, as noted by Trent in this issue of the Journal.1 While the uptake of DTC genetic testing has been relatively modest, the number of DTC genetic testing services continues to grow.2 Although the market continues to evolve,3 it seems likely that the DTC genetic testing industry is here to stay.

This reality has led to calls for regulation, with some jurisdictions going so far as to ban public access to genetic tests outside the clinical setting.4,5 In Australia, as Nicol and Hagger observe, the regulatory situation is still ambiguous;6 regulation is further complicated by the activity of internet-accessible companies that lie outside Australia’s jurisdiction. In general, the numerous policy documents that have emanated from governments and scientific and professional organisations cast DTC services in a negative light, seeing more harms than benefits, and, in some jurisdictions, governments have tried to regulate their services and products accordingly.7,8 Policy debates have focused on the possibility that DTC tests could lead to anxiety and inappropriate health decisions due to misinterpretation of the results. But are these concerns justified? Might they be driven by the hype that has surrounded the field of genetics in general. If so, what policy measures are actually needed and appropriate?

Time for a hype-free assessment of the issues?

Driven in part by the scientific excitement associated with the Human Genome Project, high expectations and a degree of popular culture hype have attracted both public research funds and venture capital to support the development of disease risk-prediction tests.3 This hype — which, to be fair, is created by a range of complex social and commercial forces9 — likely contributed to both the initial interest in the clinical potential of genetic testing and the initial concerns about possible harms. Both are tied to the perceived — and largely exaggerated — predictive power of genetic risk information, especially in the context of common diseases. There are numerous ironies to this state of affairs, including the fact that the call for tight regulation of genetic testing services may have been the result, at least in part, of the hype created by the both the research community and the private sector around the utility of genetic technologies.9 This enthusiasm helped to create a perception that genetic information is unique, powerful and highly sensitive, and specifically that, as a result, the genetic testing market warrants careful oversight.

Now that research on both the impact and utility of genetic information is starting to emerge, a more dispassionate assessment can be made about risks and the need for regulation. Are the concerns commonly found in policy reports justified? Where should we direct our policymaking energy?

It may be true that consumers of genetic information — and, for that matter, physicians — have difficulty understanding probabilistic risk information. However, the currently available evidence does not show that the information received from DTC companies causes significant individual harm, such as increased anxiety or worry.10,11 In addition, there is little empirical support for the idea that genetic susceptibility information results in unhealthy behavioural changes (eg, the adoption of a fatalistic attitude).5

The concerns about consumer anxiety and unhealthy behaviour change have driven much of the policy discussion surrounding DTC testing. As such, the research could be interpreted as suggesting that there is no need for regulation or further ethical analysis. This is not the case. We suggest that the emerging research invites us to focus our policy attention on issues that reach beyond the potential harms to the individual adult consumer — where, one could argue, there seems to be little empirical evidence to support the idea that the individual choice to use DTC testing should be curtailed — to consideration of the implications of DTC testing for health systems, children and informed public debate.

Health system costs

Although genetic testing is often promoted as a way of making health care more efficient and effective by enabling personalised medical treatment, it has been suggested that the growth in genetic testing will increase health system costs. A recent survey of 1254 United States physicians reported that 56% believed new genetic tests will increase overall health care spending.12

Will DTC testing exacerbate these health system issues by increasing costs and, perhaps, the incidence of iatrogenic injuries due to unnecessary follow-up? This seems a reasonable concern given that studies have consistently shown that DTC consumers view the provided data as health information that should be brought to a physician for interpretation. One study, for example, found that 87% of the general public would seek more information about test results from their doctor.13 The degree to which these stated intentions translate into actual physician visits is unclear. But for health systems striving to contain costs, even a small increase in use is a potential health policy issue, particularly given the questionable clinical utility of most tests offered by DTC companies. It seems likely that there will be an increase in costs with limited offsetting health benefits — although more research is needed on both these possible outcomes.

Compounding the health system concerns is the fact that few primary care physicians are equipped to respond to inquiries about DTC tests. A recent US study found that only 38% of the surveyed physicians were aware of DTC testing and even fewer (15%) felt prepared to answer questions.14 As Trent notes, even specialists can encounter difficulties in interpreting DTC genetic tests.1 This raises interesting questions about how primary care physicians will react to DTC test results. Will they, for example, order unnecessary follow-up tests or referrals, thus amplifying the concerns about the impact of DTC testing on costs?

Testing of children

While there is currently little evidence of harm caused by DTC genetic testing, most of the research has been done in the context of the adult population. The issues associated with the testing of minors are more complicated, involving children’s individual autonomy and their right to control information about themselves. Many DTC genetic testing companies include tests for adult-onset diseases or carrier status. Testing children for such traits contravenes professional guidelines. Nevertheless, research indicates that only a few DTC companies have addressed this concern. A study of 29 DTC companies found that 13 did not have policies on the issue and eight allowed testing if requested by a parent.15 While it is hard to prevent parents from submitting samples from minors to genetic testing companies, this calls for an important policy debate on whether there are limits on parental rights to access the genetic information of their children. Current paediatric genetic guidelines recommend delaying testing in minors unless it is in their best interests, but these are not enforceable and not actively monitored.16

In addition, unique policy challenges remain with regard to the submission of DNA samples in a DTC setting. It is difficult for DTC companies to check whether the sample received is from the person claiming to be the sample donor. Policymakers should consider strategies, such as sanctions, that eliminate the ordering of tests without the consent of the tested person.

Truth in advertising

The DTC industry is largely based on reaching consumers via the internet. Research has shown that the company websites — which, in many ways, represent the face of the industry — contain a range of untrue or exaggerated claims of value.17 Advertisements for tests that have no or limited clinical value have a higher risk of misleading consumers, because the claims needed to promote these services are likely to be exaggerated. It is no surprise that stopping the dissemination of false or misleading statements about the predictive power of genetics has emerged as one of the most agreed policy priorities.8 While evidence of actual harm caused by this trend is far from robust, it is hard to argue against the development of policies that encourage truth in advertising and the promotion of more informed consumers. Moreover, the claims found on these websites may add to the general misinformation about value and risks associated with genetic information that now permeates popular culture. Taking steps to correct this phenomenon is likely to help public debate and policy deliberations. For example, this might include a coordinated and international push by national consumer protection agencies to ensure that, at a minimum, the information provided by DTC companies is accurate.18

Conclusion

These are not the only social and ethical issues associated with DTC genetic testing. Others, like the use of DTC data for research and the implications of cheap whole genome sequencing, also need to be considered. But they stand as examples of issues worthy of immediate policy attention, regardless of what the evidence says about a lack of harm to individual adult users. We must seek policies that, on the one hand, allow legitimate commercial development in genomics and, on the other, achieve appropriate and evidence-based consumer protection. In finding this balance, we should not be distracted by hype or unsupported assertions of either harm or benefit.

Direct-to-consumer genetic testing — a regulatory nightmare?

Will the current framework protect consumers effectively?

The age of personalised medicine has seen the rapid emergence of a direct-to-consumer (DTC) genetic testing industry.1 While various forms of DTC testing have been available for many years, the emergence of DTC genetic testing is raising new concerns relating to the accuracy of predictions, and potential harms to consumers given there is typically no individualised genetic counselling.2 DTC testing also has the capacity to increase pressure on an already overstretched health care system if confused consumers seek assistance from health practitioners in interpreting test results.3

In Australia, a number of companies advertise genetic testing directly to consumers. While some require that a health professional orders the tests and communicates results to the consumer, others offer unmediated services. Internationally, private companies are entering the DTC genetic testing market in increasing numbers. More likely than not, Australian consumers are responding to online advertising by these companies and sending their tissue samples for analysis overseas.

There is a growing body of academic commentary internationally calling for more stringent regulation of the industry.4,5 In many countries, genetic tests are already included within regimens regulating therapeutic goods, in the form of in-vitro diagnostic medical devices (IVDs).4 However, there is ongoing debate as to whether such regimens adequately regulate DTC testing, and a lack of consistency in regulatory approaches between countries, even within Europe.6 In 2003, the Australian Law Reform Commission and Australian Health Ethics Committee concluded in Essentially yours, the report of their inquiry into the protection of genetic information, that there are “strong arguments for regulating the supply, directly to the public, of products used in some forms of genetic testing”.7 Essentially yours also canvassed the difficulties associated with regulating foreign companies offering DTC genetic testing through the internet.7

The Australian Therapeutic Goods Act 1989 (Cwlth) (the Act) applies to all therapeutic goods imported into, supplied in and exported from Australia. In 2002 a new regulatory framework was established for medical devices through the Therapeutic Goods (Medical Devices) Regulations 2002 (Cwlth) (the Regulations). Amendments to the Regulations in 2010 introduced an IVD regimen for genetic tests.

In this article we provide a brief overview of how this new regimen regulates IVDs, and some thoughts on its likely effect on DTC genetic testing. It is not our intention to add to the extensive debate surrounding the ethical and legal implications of DTC testing, or to take a position on the appropriate regulatory response.

Therapeutic Goods Act and in-vitro medical devices

The new framework was designed to ensure that all IVDs supplied in Australia, with a few limited exceptions and exclusions, are registered on the Australian Register of Therapeutic Goods (ARTG). IVDs are defined broadly in the Regulations, embracing any medical device used to examine specimens derived from the human body for therapeutic purposes. This definition excludes IVDs used for testing parentage or for detecting the presence of drugs in samples from sportspeople.8 However, genetic tests used for any health-related purposes fall within the definition, whether for detecting disease, predisposition to a particular condition or even for nutrigenomic purposes.9

IVDs are classified according to a four-tiered risk-based system, with Class 4 IVDs posing the greatest risk to public or individual health. All genetic tests are Class 3 IVDs and are required to comply with essential principles relating to quality, safety and performance. There are three categories of IVDs: all IVDs that are intended for therapeutic use, in-house IVDs and IVDs for self-testing.8 In-house IVDs are for use specifically within laboratories. Reagents, calibrators and other equipment and materials used in DTC testing all seem likely to fit within this definition. Conversely, specimen receptacles provided to consumers fall outside the in-house category. As a general rule, these receptacles come within the broad low-risk category of Class 1 IVDs. However, receptacles used in DTC testing appear to also fall within the definition of self-testing IVDs, which includes IVDs intended to be used “in the collection of a sample by a lay person and, if the sample is tested by another person (eg, a laboratory) the results are returned directly to the person from whom the sample was taken”.10

Regulatory developments, which we discuss in the next section, lend weight to the argument that the drafters intended to classify DTC receptacles as a form of self-testing IVD; however, whether this is the case remains uncertain.

Prohibition on self-testing in-vitro devices

Although the Act allows for certain self-testing IVDs to be included on the ARTG, the 2010 Therapeutic Goods (Excluded Purposes) Specification (the Specification) prohibits the supply of self-testing IVDs used for four specific purposes, including genetic testing for the presence of or susceptibility to serious diseases.11

This does not affect genetic testing mediated by health professionals, as devices used for this purpose do not come within the definition of self-testing IVDs. However, the specific inclusion of genetic testing raises the question of whether the new regimen was intended to prohibit DTC testing in Australia. Unfortunately, the Explanatory Statement to the Specification is quite vague regarding its rationale and proposed effect.12

Prohibiting the supply of self-testing IVDs in Australia

Although the 2010 Specification prohibits registration of self-testing IVDs for genetic testing purposes, it does so only if the IVD is used exclusively for the listed purpose.11 Many companies that supply IVDs to consumers for DTC genetic testing provide other related services, such as ancestry, parentage, nutrigenomic or dietary testing. Thus, one saliva sample can provide the customer with both disease susceptibility and ancestry information. Moreover, some DTC testing companies state that they do not test for disease susceptibility, but rather, their services are for informational purposes. It seems likely, then, that the prohibition in the Specification could be avoided relatively easily.

Prohibiting the import and export of self-testing IVDs

Under section 41MI of the Act, it is a criminal offence to import or export an IVD that has not been included in the ARTG. Potentially, this provision could make consumers of foreign DTC services liable on the basis that they are directly involved in the import and export of specimen collection kits. However, under item 1.1 in Schedule 4 of the amended Regulations, a medical device that is imported into Australia is an “exempt device” where it is “for use in the in vitro examination of a specimen obtained from the importer or a member of the importer’s immediate family”.13 Item 1.2 in Schedule 4 of the amended Regulations provides that a medical device exported from Australia is similarly exempt provided inter alia that it “is not intended for commercial supply” or “for use for experimental purposes on humans”.13 These provisions seem to protect Australian consumers of overseas DTC genetic testing services from criminal liability. In France, in contrast, consumers face criminal liability for requesting genetic tests “outside the conditions laid by the law”.6

Thus, it appears that the Specification will either have no effect on DTC companies, whether Australian or not, or it will apply discriminately to Australian DTC companies despite the absence of any relevant difference in the services offered by them and those offered by overseas companies.

Regulating in-house genetic testing

Come what may, the 2010 amendments to the Regulations will result in more stringent regulation of Australian companies offering genetic testing services because of the requirement that in-house IVDs be included on the ARTG (although this requirement does not come in force until 1 July 2014). Schedule 3 of the Regulations provides detailed information on the requirements imposed on manufacturers of certain classes of in-house IVDs.

As such, although it is unclear whether or not Australian-based companies are prohibited from offering DTC genetic testing, they will be scrutinised more closely come mid 2014. However, the issue of how to regulate foreign providers of DTC genetic testing services remains unresolved. One option that was canvassed in Essentially yours was the enactment of federal legislation, similar to that in place for offensive material and interactive gambling, to regulate advertising of DTC genetic testing on the internet. However, it was ultimately concluded that it would be premature to implement a similar regimen at this stage.7

Conclusion

The growing chorus of concerns about an unregulated DTC testing industry makes it increasingly difficult to argue against some form of regulation. It is unfortunate that the new Australian regimen for regulating IVDs tends to err on the side of opaqueness. Moreover, although the Australian regulatory regimen was intended to be compliant with international norms, until there is global harmonisation, the Australian regimen is likely to be as ineffective as the regimen established to deal with offensive content online. Short of restricting access to certain internet content in Australia, no further means for regulating offshore testing have been canvassed to date. It seems timely to explore the applicability of consumer protection and other laws more fully, and to encourage involvement of bodies such as the Australian Competition and Consumer Commission. In parallel, further work needs to be done to improve consumer education about genetic testing.

Is autism one or multiple disorders?

From the earliest description of autism in 1943 to the present day, there has been a widely held view that the behavioural anomalies associated with the disorder occur more often together than would be expected by chance, and therefore there will be a single causal pathway that explains the non-random co-occurrence of these symptoms.1 The phenotypic variability of autism has proved to be a major stumbling block for aetiological research. The heterogeneity spans the entire range of intelligence quotients (IQs) and language abilities, as well as other behavioural, communicative and social functions. While any psychiatric condition is likely to incorporate a degree of heterogeneity, the variability in the nature and severity of behaviours observed in autism is thought to exceed that of other disorders.1,2 The variety of presentations of people with autism is described in the Box.

Major advances in aetiological research have been made over this period; most notably, the discovery from twin studies of greater concordance for autism among monozygotic (70%–90%) compared with dizygotic (0–10%) twin pairs, providing clear evidence that the disorder is, at least in part, genetic in origin.3 However, after seven decades of intense investigation, the research community is yet to identify proximal (neurobiological) or distal (genetic and environmental) causes that lead to the full constellation of behaviours seen in all individuals with an autism diagnosis.

One response by researchers to this failure to explain behavioural variability has been to seek out biological subgroups within the broader population of people with autism. However, these studies have generally underperformed, with only weak evidence that subgroups formed around IQ, age at first word or verbal ability yield a more genetically homogenous population. A second response, which has been gaining increasing momentum, has been to reconsider our understanding of what “autism” is. In particular, there has been a proposal to move away from conceptualising autism as a unitary disorder with a large spectrum, to viewing it as a syndrome of multiple and separate disorders4 — in essence, re-examining “autism” as “the autisms”.

An instructive example here is cerebral palsy. In the mid 19th century, cerebral palsy was thought to be a unitary disorder caused by anoxia secondary to trauma occurring during labour and delivery. However, the variability in the nature of impairment between individuals with cerebral palsy, spanning varying degrees of motor, intellectual and sensory difficulties, led researchers to hypothesise that there may be many causal pathways, with only a minor proportion of cases being a direct result of perinatal hypoxia. Other identified causes include a range of genetic syndromes, neuronal migration disorders, complications of preterm birth, infections and inflammation in utero, and postneonatal causes such as bacterial meningitis.5 Contemporary international agreements for diagnosis therefore emphasise that cerebral palsy is an umbrella term covering a wide range of syndromes that arise secondary to a variety of brain lesions or anomalies occurring early in development.6

Current evidence suggests that autism may also best be conceptualised as an umbrella term for a collection of behavioural disorders resulting from a range of causal pathways. It has been estimated that autism has a known genetic aetiology in 10%–15% of diagnosed individuals, but the loci and nature of these lesions vary, from known syndromes to observable cytogenetic lesions and rare de-novo mutations (eg, copy number variations).7 Among the remaining cases of autism, no single genetic risk variant has been found to occur in more than 1% of individuals.7 Similarly, environmental risk factors identified through epidemiological studies — such as in-utero exposure to selective serotonin reuptake inhibitors8 and traffic pollution9 — differ considerably in the hypothesised biological paths to disorder, and as yet, no known environmental exposure is deterministic of autism.

Given that diagnosis is currently based on behaviour, the question of whether autism is one or multiple disorders is ultimately one about the neurobiological causes of these behaviours. It remains to be determined whether:

genetic and environmental risk factors “fan in” on a common neurobiological substrate, such as the posterior superior temporal sulcus, that has the capability of underpinning the considerable behavioural heterogeneity in autism (one disorder); or
a combination of genetic and environmental risk factors affect different brain regions and functions, which in turn prescribes the behavioural profile of each individual (multiple disorders).

A key research aim will be to investigate the correspondence (if any) between known genetic/environmental risk factors and neurobiological risk factors for autistic behaviours, using increasingly sophisticated environmental monitoring, genetic sequencing, and neuroimaging techniques.

Elucidating the underlying nature of the disorder(s) is a crucial step towards tailoring intervention to the biological and cognitive makeup of each individual. A recent study in the United States has provided clear evidence that intense and sustained behavioural therapy based on applied behavioural analysis principles can alter the neurological responses of children with autism to social stimuli, such as faces.10

For the future, we can certainly hold the hope that these treatment effects would be even more pronounced once therapy is targeted to the neural substrates subserving autistic behaviours. However, to get to this point, the question that research must answer is whether these neuropathways are the same for every individual who receives a diagnosis of autism.

Variable presentations of people with autism

Feature	Range of presentations
Communication	Non-verbal to fluent verbal language
Eye contact	Poor to excellent
Repetitive behaviours	Low frequency/intensity to very high frequency/intensity
Motor skills	Poor to excellent
Intelligence quotient	Very low to very high
Sleep	No difficulty to significant difficulty