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Genetic Testing 101

Easy Access to Our DNA Is Changing Medicine and Research

Stethoscope in the shape of a double helix SOURCE: Jane Ades, NHGRI With new opportunities come questions about how to interpret the avalanche of genetic information and how to protect it from improper use.

This Saturday, Title II of the Genetic Information Nondiscrimination Act goes into effect. This means that most employers will not be able to make decisions regarding hiring, firing, promotions, compensation, or terms of employment based on genetic information. Also, aside from a few specific exceptions, employers will not be allowed to knowingly request, require, purchase, or acquire an employee’s genetic information. In light of this milestone, it’s worth examining the current landscape of genetic testing.

What is genetic testing?

Every person’s unique genetic makeup determines many of his or her individual traits. Some of these traits—like the color of our eyes, hair, and skin—are visible to the naked eye and strongly linked to genes in our DNA. But many genes play a role in determining traits we cannot see, such susceptibility to disease or how our bodies react to various chemicals. Scientists have understood for years the direct link between certain genes and specific diseases, but as our understanding of human genetic variation improves and the cost of genetic testing drops, new possibilities for personalized medicine arise. But along with these opportunities come questions about how to interpret the avalanche of genetic information and how to protect it from improper use.

Genetic testing is not new. Scientists identified the genetic mutation that causes Huntington disease, a progressive and fatal brain disorder, in 1993. In recent years, companies began marketing tests for mutations in the BRCA1 and BRCA2 genes that indicate an increased risk of breast and ovarian cancer. But over the past few years, steep reductions in the cost of gene sequencing technology have allowed companies to offer direct-to-consumer genetic testing. These new companies may help drive the expansion of personalized medicine, but proper oversight is necessary because these new tests raise policy questions about privacy, safety, and their usefulness in clinical decision-making. According to the National Center for Biotechnology Information’s GeneTests website, there are now genetic tests available for over 1,800 diseases.

What are the different uses of genetic tests?

Genetic tests serve a variety purposes. Some diagnose a disease after symptoms have manifested themselves. Some are aimed at predicting the likelihood of a disease. Others predict the likely effectiveness of a drug or treatment based on an individual’s genes—this is known as pharmacogenomics. Tests for carrier status look for disease-related genes that parents may pass on to their children even though the parents do not have the disease. Genetic tests for newborns can determine if they need immediate intervention for a preventable or treatable condition such as phenylketonuria, a metabolic glitch that, if left unaddressed, would result in mental retardation or other serious problems, but that can be completely averted with proper dietary adjustment.

Genetic tests can also be conducted on an embryo created through in vitro fertilization before it is transferred into a uterus. This same process is referred to as preimplantation genetic screening when is used to select embryos that have chromosomal defects that may prevent them from surviving an entire pregnancy. This screening process is referred to as preimplantation genetic diagnosis when it is used to select against an embryo with a disease, condition, or—more controversially—an undesirable physical or mental trait. An IVF clinic in California called the Fertility Institute has even advertised that it can select embryos based on gender, eye color, hair color, and skin tone. But after several weeks of heated reactions to this advertisement, the institute suspended its program.

Direct-to-consumer, or DTC, genetic tests allow patients and consumers to bypass their doctors altogether and obtain a test from a company over the internet. These companies include 23andMe, Navigenics, DeCode (which has recently filed for Chapter 11 bankruptcy), and Pathway Genomics. These companies offer whole-genome scans for a few hundred dollars. Some also offer genetic tests for specific diseases or conditions as well as ancestry testing. Usually, these DTC tests utilize statistical techniques that provide a significant amount of information about a genome by only scanning a few hundred thousand molecular units (or nucleotides) out of the six billion units that comprise the human genome. The company Knome will sequence every nucleotide—or chemical unit of DNA—in an individual’s genome for $100,000. The companies that offer these DTC tests do not consider them medical products. Nevertheless, some have been known to tout their employment of on-staff physicians and genetic counselors to review customer orders.

Some Internet-based companies offer nutrigenomic tests, which purport to determine what kinds of foods you should be eating based on your genome. However, a Government Accountability Office investigation led to a scathing 2006 report on the industry. The report found that many of the tests gave recommendations that were “ambiguous” and “medically unproven.” Some of the tests were also attached to advertisements for ineffective dietary supplements, and some of the supplements had price tags of as much as $1,200 a year.

How will genetic tests change medicine and how are they already changing it?

Many researchers and clinicians anticipate that genetic tests will aid in the development of new drugs and treatments tailored to patients with specific genetic profiles. The government, private industry, and the medical community still have lots of work to do on research, administrative reorganization, and devising new protocols to make personalized medicine a reality and to make the incorporation of genetic information into regular medical decision making safe, meaningful, and effective. The recent report, “Paving the Way for Personalized Medicine,” explains these issues in detail.

According to a recent survey, 15 percent of healthcare providers reported that at least one patient brought them DTC genetic test results in the past year. Of those providers, 75 percent changed some aspect of their patient’s care based on the test results. This reaction by the clinicians demonstrates a disconnect between the clinical community and the research community on the perceived effectiveness of genetic tests. The research community believes that current studies have only found a small fraction of the genetic components of most conditions. Additionally, there is scant evidence that genetic tests lead to changes in treatment that improve health outcomes, also known as clinical utility. At this point, there are multiple views concerning the level of encouragement physicians should be giving their patients about adopting DTC genetic testing as a guide for personal health care. Some feel that physicians should wait until there are more comprehensive studies about the clinical outcomes of genomic medicine. Others argue that physicians should encourage prevention with genetic tests and teach their patients about the science as it develops so that they do not seek information from other and possibly less-reliable sources.

Geneticist J. Craig Venter recommends in a recent Nature article that companies report the proportion of disease risk attributable to genetic markers, focus on diseases and traits with high-risk predictions, and agree on a set of strong-effect genetic markers for specific conditions.

What are the privacy concerns?

Thanks to the passage Genetic Information Nondiscrimination Act of 2008, employers and health insurance companies cannot obtain an individual’s genetic information without his or her consent and cannot use an individual’s genetic information to deny that individual a job, promotion, or health insurance coverage. Unfortunately, these federal protections do not extend to disability insurance, long-term care insurance, and life insurance. However, 16 states regulate the use of genetic information in life insurance; 16 states regulate its use in disability insurance; and 10 states regulate the its use in long-term care insurance. Of course, these policies all vary from state to state.

Many of the companies offering direct-to-consumer genetic testing also compile databases of genetic information that they gather from their customers. This is the second major component of their business model, as the data is valuable for advancing genetic research. But informed consent process for this information raises new, complex issues.

In an interview with Science Progress, Stanford bioethicist Sandra Lee explained the consent processes that some of these companies have adopted for using or selling their customers’ genetic data for research purposes. Some have adopted policies of “open consent” where a customer agrees to allow research on their genetic data for any studies in the future. This marks a break with the traditional rules of informed consent in clinical trials where all potential uses of the subject’s information must be disclosed. Navigenics has adopted a policy of asking customers to opt-in to research and then provide new consent forms to customers every time a new study arises. 23andMe also has a similar consent policy wherein they provide individual data to their research partners.

Most informed consent forms for genetic research indicate that a subject’s genetic information will be de-identified by separating the genetic information from the subject’s name and other personal information. Of course, some studies focus on the links between genes and other identifying information like ethnicity, family history, or disease status; and the informed consent forms tend to vary from study to study.

One of the most common types of genetic studies is the genome wide association study, commonly referred to as a GWAS. In a this type of study, scientists take a group of people who possess a certain phenotype—an observable characteristic or a trait like height, a condition like hypertension, or a disease like cancer—and compare them with a group of people without that phenotype. The scientists look at hundreds of thousands of single units of DNA known as single nucleotide polymorphisms or SNPs. Whichever SNPs are more likely to be present in the people who possess the phenotype and absent in those without it are considered associated SNPs. An associated SNP is not directly responsible for the phenotype, though it does indicate that the genetic sequence that is responsible may lie somewhere nearby on the genome. Scientists will then examine the relevant section of the genome and attempt to identify the exact sequence that is responsible.

The hope of many researchers is that with the passage and enforcement of GINA, more people will volunteer for genomic research. GINA is needed now more than ever since even though researchers remove subject names and other identifiers from the genetic data they collect, researchers demonstrated in 2008 that it is nonetheless possible to work backward from a common pool of de-identified genetic information and identify individuals in a database. As a result, the National Institutes of Health implemented stronger security controls for their GWAS databases.

How do scientists or regulators assess the reliability of genetic tests?

In order for genetic tests to have a meaningful impact on medicine, they need to be rigorously assessed and held to transparent empirical and clinical standards. Not only do the labs and diagnostic manufacturers need to demonstrate that the tests they conduct can reliably find the genes they purport to look for, researchers also need to show that once the genes are detected by a test, they can reliably predict a phenotype and help to inform treatment decisions in a way that improves health. This is a tall order to say the least, but scientists and regulators assess tests according to three criteria: analytical validity, clinical validity, and clinical utility.

  • Analytical validity is the ability of a test to find a specific genetic sequence, broadly referred to as the “analyte.” Genes are different from other analytes like proteins, which can be present in varying amounts, since a gene is either present or absent.
  • Clinical validity is the probability that you will get a disease if you test positive and that you will not get the disease if you test negative. The probability that a disease will appear if a disease-related gene is found is called the penetrance of the gene.
  • Clinical utility is the ability of a genetic test’s results to lead to a course of action or interventions that result in improved health outcomes.

A coalition of researchers has also proposed a fourth criterion called personal utility. Research on this criterion would assess the patient’s or population subgroup’s perception of the advantages of genetic testing and whether it would affect the patient’s behavior and subsequent clinical utility of the genetic test. The social considerations and metrics for this criterion are still under development.

What are the gaps in the oversight of direct-to-consumer genetic tests?

Aside from the federal Clinical Laboratory Improvement Act regulations and limited Food and Drug Administration rules, most lab regulation has been left up to the states. Many policymakers, bioethicists, and representatives from the DTC industry feel that this patchwork of state regulations is not sufficient and that the lack of federal oversight has left a gaping hole in the regulatory framework. Two pieces of legislation that would regulate genetic testing and labs have long been on the Congressional back-burner: the “Genomics and Personalized Medicine Act of 2007” sponsored by then-Senator Obama and the “Laboratory Test Improvement Act of 2007” sponsored by the late Senator Edward Kennedy. Ultimately, whether through legislation or simply new regulatory protocols, this regulatory gap can easily be filled by four measures that will allow for the federal oversight of genetic tests, the labs that conduct them, the transparency of their results, and the advertising of direct-to-consumer genetic tests. The Center for American Progress and the Genetics and Public Policy Center have made these recommendations:

  1. Have the Centers for Medicare and Medicaid Services, or CMS, create a “specialty” for genetic testing laboratories.
  2. Expand the FDA’s jurisdiction to include the regulation of lab-developed tests in addition to pre-manufactured test “kits” that already fall under its jurisdiction.
  3. Create a mandatory genetic test registry so that the clinical validity of all genetic tests is transparent for the public.
  4. The FDA and FTC should collaborate on curtailing false or misleading advertising by genetic testing companies in accordance with Section 5 of the FTC Act.

Last year, 23andMe collaborated with Navigenics, de CODE, and the Personalized Medicine Coalition to release a statement outlining the standards they would like to see governing the scientific validity of DTC genetic tests. A recent panel convened by the Centers for Disease Control and Prevention and NIH welcomed their input but also advocated independent assessments from the Depart of Health and Human Services U.S. Preventive Services Task Force or the CDC’s Evaluation of Genomic Applications in Practice and Prevention. Both the governmental and private groups are moving ahead with their standard-setting and assessment efforts, but it remains to be seen rules will materialize.

Michael Rugnetta is a research assistant with the Progressive Bioethics Initiative at the Center for American Progress.

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