This is the Meaning of Life? Genes, Genomes, and DTC Genetic Testing

Genetic testing

In 2000, the heads of two research consortia (one publicly funded, the other private) fronted a press conference at the White House as the then- President of the United States of America, Bill Clinton, announced that the first draft of the entire human genome was complete.

For biologists, this milestone was viewed as the equivalent to man landing on the moon, heralding a new era of genomic medicine, whereby analysing the genomic sequence of specific individuals would reveal susceptibility to medical conditions, permit tailoring of treatments for disease based on the individual’s genetic make-up, provide myriad other diagnostic and therapeutic benefits or simply address a market for “designer babies”.^[596]

Amid talk of a “genomics gold rush”,^[597] ready access to venture capital and the absence of systematic regulation over the past decade resulted in the emergence of a range of start-up DTC testing enterprises located in the US, Iceland and other jurisdictions.^[598] They have been marketing their services worldwide, synergising with celebrity events, corporate websites, invitations in social network services and co-marketing through partnerships with bodies that range from the US National Geographic Association to Australian private health insurer NIB. Marketing strategies have very much focused on forming partnerships with credible entities, to detract attention from the lack of scientific data underpinning the tests themselves.^[599]

Despite these high hopes, and the expansion of commercial research in the area, sequencing of the human genome is yet to yield some of the expected breakthroughs.

The human genome and disease

The human genome consists of three billion bases — pairs of chemical molecules — arranged in sequence to form genes. These sequences are then further packaged as chromosomes, of which humans have 22 pairs, and the two sex chromosomes, XX for women, and XY for men. Each chromosome carries a copy of each of the genes located on that chromosome, again with the exception of the sex chromosomes — women have two copies, one on each of the X chromosomes, while men only have a single copy, only having one X chromosome. Genes frequently act as a template or pattern for proteins — other molecules — that perform specific functions within the cell. Errors within the sequence can either lead to the protein produced being incorrect, or may affect the production or distribution of that protein.

According to the simplest models of disease caused by genetics, a single defect within a gene — potentially as minor as one error affecting a single base in the sequence of three billion bases — directly causes a change in how the cells of the body function, ultimately causing disease. This is most obvious in sex-linked disorders, such as haemophilia, where males, having only a single copy of the affected X-chromosome located gene, are affected much more severely and frequently than their female relatives; however for other genes, if a person has mutations within the both copies of an autosomal gene they can develop a wide range of disorders.

A large number of diseases do not follow this simple model. Increasingly, genome wide association studies (GWAS) are being used to identify candidate regions within the genome that appear to be associated with certain diseases. However, in many cases it is not entirely clear whether the region identified is a cause of the disease, or merely correlates with it, and these tests fails to detect the interactions between products of multiple genes, or account for environmental factors contributing to disease development.^[601] Consequently, GWAS data, rather than providing a simple yes/no answer to the question of whether an individual will develop a disease, tends to rely on complex statistical analysis to determine whether a particular individual is at increased risk of developing a condition based on a combination of factors, both genetic and environmental. While useful in revealing genetic targets suitable for further research, they are not definitive diagnostic tools.

Many of the companies operating in this market utilise GWAS-derived testing platforms, such as microarrays or other high through-put technology, and market them directly to consumers, either directly, or by implication. In doing so, DTC providers are implicitly overstating the clinical validity and utility of these platforms. Companies frequently use commercially available testing platforms, such as Affymetrix and Illumina microarray and single nucleotide polymorphism chips, as the basis of their testing. It is worth noting, however, that the commercial market for which these platforms are designed was traditionally the life-sciences research market, rather than the clinical diagnostic market. The very fact that the platforms are commercially available does not, as some consumers assume, mean that the testing platforms themselves have been approved for diagnostic use — they have not — or that the test results are readily interpretable.

Although tests for some multifactorial conditions have been validated by scientific evidence and are now used as legitimate clinical diagnostic tools, in many cases the associations between gene variants and altered risk of developing diseases, in isolation from other risk factors, are currently too weak to be of clinical significance, and are, at best, indicative only, rather than predictive.

The ability to generate a complete and reliable predictive profile of a person’s health, intelligence, physical appearance, and other attributes simply from the sequence of their DNA remains, therefore, a scientific impossibility at the present time, due to the substantial gaps in knowledge, including about models of complex multi-gene and environmental factor interactions.

The traditional business model for DTC testing consisted of a potential client registering interest with a company, often via a website, which would then send a collection kit to the address of the client. The kit contained a collection vessel, and sometimes a swab. The client then either self-administered a buccal swab — brushing the inside of the cheek to collect epithelial cells — or simply spat into the collection vessel, which was then mailed back to the testing facility of the company. In exchange for fees, the company performed genetic sequencing tests against the genetic markers of the client’s choice, and the company then produced a report summarising the findings. The client was frequently required to access their results via a login website, and pay an ongoing subscription fee in order to maintain their access to their results. Although some sites provided access to genetic counsellors, often via telephone or email, this was by no means always the case.

Regulation: Who has the power?

Most Western jurisdictions — notably Australia, the US, Canada, Japan, and the EU — have regulatory bodies who are authorised by law to regulate pharmaceuticals and medical products. Their powers include granting or withholding regulatory approval for marketing. In the event that approval is not forthcoming, generally the product cannot lawfully be marketed in that country, noting that there are some exceptional circumstances which are recognised.

DTC genetic tests meet the criteria for in vitro diagnostic devices which fall within the purview of these regulatory agencies.

IVD medical device, or in vitro diagnostic medical device, means a medical device that is:

(a) a reagent, calibrator, control material, kit, specimen receptacle, software, instrument, apparatus, equipment or system, whether used alone or in combination with another diagnostic product for in vitro use; and

(b) intended by the manufacturer to be used in vitro for the examination of a specimen derived from the human body, solely or principally for:

(i) giving information about a physiological or pathological state or a congenital abnormality; or

(ii) determining safety and compatibility with a potential recipient; or

(iii) monitoring therapeutic measures; and

(c) not a product that is:

(i) intended for general laboratory use; and

(ii) not manufactured, sold or presented for use as an IVD medical device.^[602]

Clearly, therefore, a DTC collection kit from a company running tests which can provide information about a client’s likely risk of developing a particular condition will appear to meet these criteria and, logically, should fall under the notice of the relevant regulator.

Once it has been established that a test is an in vitro diagnostic medical device, the regulator considers whether it should receive approval, permitting it to be marketed in that jurisdiction. Such approval for devices, including genetic tests, will only be granted if the applicants can demonstrate that the test is both safe and effective for patient use: safe, meaning that it will not cause the patient harm — and effective — meaning that it does what it claims to do, based on scientific data.

The majority of tests being marketed by DTC genetic testing companies are generally “safe”: the consumer is not exposed to any test reagent, and swabbing the inside of the mouth to obtain buccal cells, and mailing the swab to the company in a sealed container poses little physical risk to the consumer.

Tests for diseases following the simpler model, based on mutations in a single gene, discussed above, generally have a high predictive power. Based on the genetic sequence of an individual, conclusions can be drawn about whether they will or will not develop that disease. Such tests are both clinically valid — they accurately predict disease — and clinically useful — they provide information that, in many cases, is relevant for treatment.

As the model becomes more complex, and more factors are involved in development of disease, the predictive power of genetic testing decreases markedly, and results are instead expressed in terms of risk. Rather than providing a determinative yes or no type answer, they consider the increased or decreased risk associated with a genetic sequence, either with or without consideration of confounding factors such as the role of other genes and environmental factors involved in development of the disease. Analysis of risk associated with confounding factors is complicated by the incomplete identification of all contributing factors in many instances. For many diseases, it is clear that although there is a genetic component associated with risk of developing disease, other as-yet unidentified risk factors, including other genes, also have a role to play. The majority of tests marketed DTC are of the latter type.

Yet despite legitimate concerns frequently expressed about the validity and utility of these tests by the scientific community,^[604] and the fact that, prima facie, they appear to fall squarely within the scope of regulation, until recently, providers of DTC genetic testing generally escaped the detailed attention of the regulators. That inattention reflected the newness of the technologies, resourcing and other problems within bodies such as the FDA and TGA, the absence of an incident that gained bureaucratic/media attention and thus affected institutional priorities, and the strategic location of some genetic testing services within jurisdictions (such as Iceland) with weak privacy and clinical regulatory frameworks.

Gertz, for example, notes

legislation passed by the Icelandic government not for the benefit of scientists in general, but for one specific commercial company and enabling deCODE Genetics, a firm registered in the USA and based in Iceland, to set up a database consisting of the medical and genealogical records of the entire Icelandic population, living and dead, as well as tissue samples of every living Icelander.^[605]

This lack of regulatory attention abruptly ground to a halt in mid-2010, when the business model of DTC providers evolved in a way that made it impractical for regulators in the US to ignore it any longer. Pathways Genomics announced that it was further advancing its business model by selling collection kits directly on shelves at Walgreen’s drugstores throughout the US, finally prompted the US government, and the FDA in particular, to investigate DTC genetic testing.