Genetic Testing: Scientific Background for Policymakers
Genetic Testing:
Scientific Background for Policymakers
Updated January 30, 2008
Amanda K. Sarata
Analyst in Genetics
Domestic Social Policy Division
Genetic Testing:
Scientific Background for Policymakers
Summary
In the 110th Congress, several pieces of legislation have been introduced that
relate to genetic and genomic technology and testing. These include bills addressing
genetic discrimination in health insurance and employment, personalized medicine,
the patenting of genetic material, and the quality of laboratory tests. The introduction
of these bills signals the growing importance of the public policy issues surrounding
the clinical and public health implications of new genetic technology. As genetic
technologies proliferate and are increasingly used to guide clinical treatment, these
public policy issues are likely to continue to garner considerable attention.
Understanding the basic scientific concepts underlying genetics and genetic testing
may help facilitate the development of more effective public policy in this area.
Most diseases have a genetic component. Some diseases such as Huntington’s
Disease are caused by a specific gene. Other diseases, such as heart disease and
cancer, are caused by a complex combination of genetic and environmental factors.
For this reason, the public health burden of genetic disease is substantial, as is its
clinical significance. Experts note that society has recently entered a transition
period in which specific genetic knowledge is becoming critical to the delivery of
effective health care for everyone. Therefore, the value of and role for genetic testing
in clinical medicine is likely to increase significantly in the future.
Contents
In troduction ......................................................1
Fundamental Concepts in Genetics....................................2
Cells Contain Chromosomes.....................................2
Chromosomes Contain DNA.....................................3
DNA Codes for Protein.........................................3
Genotype Influences Phenotype...................................3
Genetic Tests.....................................................4
What is a Genetic Test?.........................................4
Policy Issues..............................................4
How Many Genetic Tests are Available?............................4
What are the Different Types of Genetic Tests?......................5
Policy Issues..............................................6
The Genetic Test Result.........................................6
Policy Issues..............................................7
Characteristics of Genetic Tests...................................7
Policy Issues..............................................8
Coverage by Health Insurers.....................................9
Policy Issues..............................................9
Regulation of Genetic Tests by the Federal Government...............9
Genetic Testing:
Scientific Background for Policymakers
Introduction
Virtually all disease has a genetic component.1 The term “genetic disease” has
traditionally been used to refer to rare monogenic (caused by a single gene) inherited
disease, for example, cystic fibrosis. However, we now know that all complex
diseases, including common chronic conditions such as cancer, heart disease and
diabetes, are the product of some combination of genetic and environmental factors.
For this reason, they could all be said to be “genetic diseases”. Considering this
broader definition of genetic disease, the public health burden of genetic disease can
be seen to be substantial. In addition, an individual patient’s genetic make-up, and
the genetic make-up of his disease, will help guide clinical decision making. Experts
note that “(w)e have recently entered a transition period in which specific genetic2
knowledge is becoming critical to the delivery of effective health care for everyone.”
For this reason, the value of and role for genetic testing in clinical medicine is likely
to increase significantly in the future. As the role of genetics in clinical medicine and
public health continues to grow, so will the importance of public policy issues raised
by genetic technologies.
Science is only beginning to unlock the complex nature of the interaction
between genes and the environment in common disease, and their respective
contributions to the disease process. The information gleaned from the Human
Genome Project will help, and is currently helping, scientists and clinicians to
identify common genetic variation that contributes to disease. In addition, research
conducted utilizing large population databases that collect health, genetic, and
environmental information about entire populations will likely provide more
information about the genetic and environmental underpinnings of common diseases.
Many countries have established such databases, including Iceland, the United
Kingdom, and Estonia. The knowledge of the potential relevance of genetic
information to the clinical management of nearly all patients coupled with the lack
of complete information about the genetic and environmental factors underlying
disease creates a challenging climate for public policymaking.
In many cases, the results of genetic testing may be used to guide clinical
management of patients. For example, more frequent screening may be
recommended for individuals at increased risk of certain diseases by virtue of their
1 Collins, F.S. and V.A. McCusick. (2001) “Implications of the Human Genome Project for
Medical Science.” Journal of the American Medical Association 285:540-544.
2 Guttmacher, A.E. and F.S. Collins. (2002) “Genomic Medicine - A Primer.” New England
Journal of Medicine 347(19): 1512-1520.
genetic make-up, such as colorectal and breast cancer. In some cases, prophylactic
surgery may even be indicated. Decisions about courses of treatment and dosing may
also be guided by genetic testing, as might reproductive decisions (both clinical and
personal). However, many diseases do not have any treatment available (for
example, Huntington’s Disease). In these cases, the benefits of genetic testing lie
largely in the information they provide an individual about his or her risk of future
disease or current disease status. The value of genetic information in these cases is
personal to individuals, who may choose to utilize this information to help guide
medical and other life decisions for themselves and their families. The information
can affect decisions about reproduction, the types or amount of health, life, or
disability insurance to purchase, or career and education choices. As genetic research
continues to advance rapidly, it will often be the case that genetic testing may be able
to provide information about the probability of a health outcome without an
accompanying treatment option. This situation again creates unique public policy
challenges, for example, in terms of the financing of genetic testing services and
education about the value of testing (see S. 609, 109th Congress, for example).
Concerns about privacy and the use and misuse of genetic information, as well
as issues of genetic exceptionalism3 and genetic determinism4, may need to be
balanced with the potential of genetics and genetic technology to change how care
is delivered and to personalize medical care and treatment of disease.
This report will summarize basic scientific concepts in genetics and will provide
an overview of genetic tests, their main characteristics, and the key policy issues they
raise.
Fundamental Concepts in Genetics
The following section explains key concepts in genetics that are essential for
understanding genetic testing and issues associated with testing that are of interest
to Congress.
Cells Contain Chromosomes
Humans have 23 pairs of chromosomes in the nucleus of most cells in their
bodies. These include 22 pairs of autosomal chromosomes (numbered 1 through 22)
and one pair of sex chromosomes (X and Y). One copy of each autosomal
chromosome is inherited from the mother and from the father, and each parent
contributes one sex chromosome.
3 Genetic exceptionalism is the concept that genetic information is inherently unique, should
receive special consideration, and should be treated differently from other medical
information.
4 Genetic determinism is the concept that our genes are our destiny and that they solely
determine our behavioral and physical characteristics. This concept has mostly fallen out
of favor as the substantial role of the environment in determining characteristics has been
recognized.
Many syndromes involving abnormal human development result from abnormal
numbers of chromosomes (such as Down Syndrome). Other diseases, such as
leukemia, can be caused by breaks in or rearrangements of chromosome pieces.
Chromosomes Contain DNA
Chromosomes are composed of deoxyribonucleic acid (DNA) and protein.
DNA is comprised of complex chemical substances called bases. Strands made up
of combinations of the four bases (adenine (A), guanine (G), cytosine (C) and
thymine (T)) twist together to form a double helix (like a spiral staircase).
Chromosomes contain almost 3 billion base pairs of DNA that code for about
20,000-25,000 genes (this is a current estimate, although it may change and has
changed several times since the publication of the human genome sequence).5
DNA Codes for Protein
Proteins are fundamental components of all living cells. They include enzymes,
structural elements, and hormones. Each protein is made up of a specific sequence
of amino acids. This sequence of amino acids is determined by the specific order of
bases in a section of DNA. A gene is the section of DNA which contains the
sequence which corresponds to a specific protein. Changes to the DNA sequence,
called mutations, can change the amino acid sequence. Thus, variations in DNA
sequence can manifest as variations in the protein which may affect the function of
the protein. This may result in, or contribute to the development of, a genetic
disease.
Genotype Influences Phenotype
Though most of the genome is very similar between individuals, there can be
significant variation in physical appearance or function between individuals. In other
words, although we share most of the genetic material we have, we can see that there
are significant differences in our physical appearance (height, weight, eye color, etc.).
Humans inherit one copy (or allele) of most genes from each parent. The specific
alleles that are present on a chromosome pair constitute a person’s genotype. The
actual observable physical trait is known as the phenotype. For example, having two
brown-eye color alleles would be an example of a genotype and having brown eyes
would be the phenotype.
Many complex factors affect how a genotype (DNA) translates to a phenotype
(observable trait) in ways that are not yet clear for many traits or conditions. Study
of a person’s genotype may determine if a person has a mutation associated with a
disease, but only observation of the phenotype can determine if that person actually
has physical characteristics or symptoms of the disease. Generally, the risk of
developing a disease caused by a single mutation can be more easily predicted than
the risk of developing a complex disease caused by multiple mutations in multiple
5 National Research Council, Reaping the Benefits of Genomic and Proteomic Research:
Intellectual Property Rights, Innovation, and Public Health. Washington, DC: National
Academies Press (2006); p. 19.
genes and environmental factors. Complex diseases, such as heart disease, cancer,
immune disorders, or mental illness, for example, have both inherited and
environmental components that are very difficult to separate. Thus, it can be difficult
to determine whether an individual will develop symptoms, how severe the
symptoms may be, or when they may appear.
Genetic Tests
What is a Genetic Test?
Scientifically, a genetic test is defined as
an analysis performed on human DNA, RNA, genes, and/or chromosomes to
detect heritable or acquired genotypes, mutations, phenotypes, or karyotypes that
cause or are likely to cause a specific disease or condition. A genetic test also
is the analysis of human proteins and certain metabolites, which are
predominantly used to detect heritable or acquired genotypes, mutations, or6
phenotypes.
Once the sequence of a gene is known, looking for specific changes is relatively
straightforward using the modern techniques of molecular biology. In fact, these
methods have become so advanced that hundreds or thousands of genetic variations
can be detected simultaneously using a technology called a microarray.
Policy Issues. The way genetic test is defined is extremely important to the
development of genetics-related public policy. For example, the above scientific
definition is very broad and inclusive, but this may not be the best way to achieve
certain policy goals. It may sometimes be desirable to limit the definition only to
predictive, and not diagnostic, genetic testing (see “What are the different Types of
Genetic Tests?”). In other cases, it may be desirable to limit the definition to only
analysis of specific material, such as DNA, RNA, and chromosomes, but not
metabolites or proteins. Considerable variation in the definition of genetic test may
be found in the many state genetic nondiscrimination laws. Policies extending
protection against discrimination may aim to be as broad as possible, whereas
policies addressing coverage of genetic tests may aim to be more limited.
How Many Genetic Tests are Available?
As of January 2008, genetic tests are available for 1,513 diseases. Of those
tests, 1,225 are available for clinical diagnosis, while 288 are available for research
only.7 The majority of these tests are for single-gene rare diseases. Asked about the
6 Report of the Secretary’s Advisory Committee on Genetic Testing (SACGT), “Enhancing
the Oversight of Genetic Tests: Recommendations of the SACGT,” July 2000, at
[http://www4.od.nih.gov/oba/sacgt/re ports/oversight_report.pdf].
7 See [http://www.genetests.org] for information on disease reviews, an international
directory of genetic testing laboratories, an international directory of genetics and prenatal
(continued...)
realistic promise of genetic technology, Francis Collins, the Director of the National
Human Genome Research Institute predicted,
I think we can count on the availability within the next decade of a panel of
genetic tests that are going to be offered to all of us to determine our risk of
common illnesses, focused particularly on those diseases for which there is some8
intervention available for those found to be at high risk.
What are the Different Types of Genetic Tests?
Most clinical genetic tests are for rare disorders, but increasingly, tests are
becoming available to determine susceptibility to common, complex diseases and to
predict response to medication.
With respect to health-related tests (i.e., excluding tests used for forensic
purposes, such as “DNA fingerprinting”), there are two general types of genetic
testing: diagnostic and predictive. Genetic tests can be utilized to identify the
presence or absence of a disease (diagnostic). Predictive genetic tests can be used to
predict if an individual will definitely get a disease in the future (predictive-
presymptomatic) or to predict the risk of an individual getting a disease in the future
(predictive-predispositional). For example, testing for mutations in the BRCA1
and/or BRCA2 genes provides probabilistic information about how likely an
individual is to develop breast cancer in his or her lifetime (predispositional). The
genetic test for Huntington’s Disease provides genetic information that is predictive
in that it allows a physician to predict with certainty whether an individual will
develop the disease, but does not allow the physician to determine when the onset of
symptoms will actually occur (presymptomatic). In both of these examples, the
individual does not have the clinical disease at the time of genetic testing, as they
would with diagnostic genetic testing.
Within this broader framework of diagnostic and predictive genetic tests, several
distinct types of genetic testing can be considered. Reproductive genetic testing can
identify carriers of genetic disorders, establish prenatal diagnoses or prognoses, or
identify genetic variation in embryos before they are used in in vitro fertilization.
Reproductive testing, such as prenatal testing, may be either diagnostic or predictive
in nature. Newborn screening is a type of genetic testing that identifies newborns
with certain metabolic or inherited conditions (although not all newborn screening
tests are genetic tests). Traditionally, most newborn screening has been diagnostic,
but recently several states have added some predictive genetic testing to their panels9
of newborn screening (for example, Maryland includes testing for cystic fibrosis).
Finally, pharmacogenomic testing, or testing to determine a patient’s likely response
7 (...continued)
diagnosis clinics, and a glossary of medical genetics terms.
8 E. Rabinowitz, “Genetics in Medicine: Hype or Real Promise?” Health plan,
January/February 2003.
9 Newborn Screening Programs, Family Health Administration, Maryland Department of
Health and Mental Hygiene. [http://www.fha.state.md.us/genetics/pdf/Pamphlet_NBS.pdf].
to a medication, may be considered either diagnostic or predictive, depending on the
context in which it is being utilized.
Policy Issues. Generally, predictive genetic testing (both presymptomatic and
predispositional), rather than diagnostic testing, raises more complex ethical, legal
and social issues. For example, issues surrounding insurance coverage and
reimbursement for this type of test, especially if no treatment is available, are far
more complex than with diagnostic genetic testing. A private insurer may feel that
paying for a test that predicts the onset of a disease with no treatment is not cost-
effective. Even more complicated are cases where the test only shows an increased
probability of getting a disease. In addition, Medicare’s screening exclusion means
that this type of test generally will not be covered for the elderly population.10
Another issue is the oversight of genetic tests. Strong oversight of genetic tests
may be more important where the information is probabilistic rather than diagnostic
and when a treatment is not available. Finally, issues of genetic discrimination may
be different with predictive testing than they are with diagnostic testing. Genetic
discrimination may be defined as differential treatment in either health insurance
coverage or employment based upon an individual’s genotype. Discriminatory action
based on the possibility of something happening in the future, or even the certainty
of it happening in the future, might raise more concern than would action taken based
upon diagnostic information. With probabilistic genetic information, the health
outcome of concern may never manifest, or if it is certain to, may not manifest for
decades into the future.
The Genetic Test Result
Genetic tests can provide information about both inherited genetic variations,
that is, the individual’s genes that were inherited from their mother and father, as
well as about acquired genetic variations, such as those that cause some tumors.
Acquired mutations are not inherited, but rather are acquired in DNA due to
replication errors or exposure to mutagenic chemicals and radiation (e.g., UV rays).
DNA-based testing of inherited genetic variants differs from other medical
testing in important ways: it can have exceptionally long-range predictive powers
over the lifespan of an individual; it can predict disease or increased risk for disease
in the absence of clinical signs or symptoms; it can reveal the sharing of genetic
variants within families at precise and calculable rates; and, at least theoretically, it
has the potential to generate a unique identifier profile for individuals. Also, unlike
most other medical tests, the stability of DNA means that most genetic tests can be
performed on material from a body and continue to provide information after the
individual has died.
10 Secretary’s Advisory Committee on Genetics, Health, and Society. “Coverage and
Reimbursement of Genetic Tests and Services.” February 2006. [http://www4.od.nih.gov/
oba/sacghs/reports/CR_report.pdf]. CMS has interpreted the Medicare statute to exclude
coverage of preventive care unless specifically authorized by Congress.
Genetic changes to inherited genes can be acquired throughout a person’s life.
Tests that are performed for acquired genetic markers that occur with a disease have
implications only for individuals with the disease, and not family members. Tests
for acquired genetic changes are also usually diagnostic rather than predictive, since
these tests are generally performed after symptoms present.
Pharmacogenomic testing may be used to determine acquired genetic variations
in disease tissue (i.e., acquired variations in a tumor) or may be used to determine
inherited variations in an individual’s drug metabolizing enzymes. For example,
with respect to determining acquired variation in disease tissue, a tumor may have
acquired genetic changes that make it different from normal tissue that may also
render that tumor susceptible or resistant to chemotherapy. With respect to inherited
variation in drug metabolizing enzymes, an individual may be found to be a slow
metabolizer of a certain type of drug (statins, for example) and this information can
be used to guide both drug choice and dosing.
Policy Issues. In some cases, people feel differently about their genetic
information than they do about other medical information, a sentiment embodied by
the concept of genetic exceptionalism. This may be based on the stated differences
between genetic testing and other medical testing, but also may be based on personal
belief that genetic information is powerful and different than other medical
information. For this reason, public policies around genetic discrimination in health
insurance, employment and sometimes life insurance proliferated at the state level
in the 1990s, and genetic nondiscrimination legislation has been considered by
Congress for nearly a decade. Whether genetic information is somehow different
from other medical information; whether it can be separated logically from other
medical information; and whether it deserves special protection are all important
public policy issues.
Pharmacogenomic testing is important because it will help provide the
foundation for personalized medicine. Personalized medicine is healthcare based on
individualized diagnosis and treatment for each patient determined by information
at the genomic level. Many public policy issues are associated with personalized
medicine. For example, there is some uncertainty currently as to how health insurers
will assess and choose to cover pharmacogenomic testing as it becomes available.
In addition, there are issues surrounding the regulation of pharmacogenomic testing.
The Genomics and Personalized Medicine Act of 2007 (S. 976) considers many of
these issues.
Characteristics of Genetic Tests
Genetic tests function in two environments: the laboratory and the clinic.
Genetic tests are evaluated based primarily on three characteristics: analytical
validity, clinical validity, and clinical utility.
Analytical Validity. Analytical validity is defined as the ability of a test to detect or
measure the analyte it is intended to detect or measure.11 This characteristic is critical
for all clinical laboratory testing, not only genetic testing, as it provides information
about the ability of the test to perform reliably at its most basic level. This
characteristic is relevant to how well a test performs in a laboratory.
Clinical Validity. The clinical validity of a genetic test is its ability to accurately
diagnose or predict the risk of a particular clinical outcome. A genetic test’s clinical
validity relies on an established connection between the DNA variant being tested for
and a specific health outcome. Clinical validity is a measure of how well a test
performs in a clinical rather than laboratory setting. Many measures are used to
assess clinical validity, but the two of key importance are clinical sensitivity and
positive predictive value. Genetic tests can be either diagnostic or predictive and,
therefore, the measures used to assess the clinical validity of a genetic test must take
this into consideration. For the purposes of a genetic test, positive predictive value
can be defined as the probability that a person with a positive test result (i.e., the
DNA variant tested for is present) either has or will develop the disease the test is
designed to detect. Positive predictive value is the test measure most commonly used
by physicians to gauge the usefulness of a test to clinical management of patients.
Determining the positive predictive value of a predictive genetic test may be difficult
because there are many different DNA variants and environmental modifiers that may
affect the development of a disease. In other words, a DNA variant may have a
known association with a specific health outcome, but it may not always be causal.
Clinical sensitivity may be defined as the probability that people who have, or will
develop a disease, are detected by the test.
Clinical Utility. Clinical utility takes into account the impact and usefulness of the
test results to the individual and family and primarily considers the implications that
the test results have for health outcomes (for example, is treatment or preventive care
available for the disease). It also includes the utility of the test more broadly for
society, and can encompass considerations of the psychological, social and economic
consequences of testing.
Policy Issues. These three characteristics of genetic tests have important ties
to public policy issues. For example, although the analytical validity of genetic tests
is regulated by the Centers for Medicare and Medicaid Services (CMS) through the
Clinical Laboratory Improvement Amendments (CLIA) of 1988 (P.L. 100-578), the
clinical validity of the majority of genetic tests is not regulated at all. This has raised
concerns about direct-to-consumer marketing of genetic tests where the connection
between a DNA variant and a clinical outcome has not been clearly established.
Marketing of such tests to consumers directly may mislead consumers into believing
that the advice given them based on the results of such tests could improve their
health status/outcomes when in fact there is no scientific basis underlying such an
assertion. This issue was the subject of a July 2006 hearing by the Senate Special
Committee on Aging. In addition, clinical utility and clinical validity both figure
prominently into coverage decisions by payers, but a lack of data often hinders
coverage decisions, leaving patients without coverage for these expensive tests.
11 An analyte is defined as a substance or chemical constituent undergoing analysis.
Coverage by Health Insurers
Health insurers are playing an increasingly large role in determining which
medical tests are available by deciding which tests they will pay for as part of patient
benefit packages. Many aspects of genetic tests, including their clinical validity and
utility, may complicate the coverage decision-making process for insurers. While
insurers require that a test be approved by the Food and Drug Administration (when
required), they also want evidence that it is “medically necessary;” that is, evidence
demonstrating that a test will affect a patient’s health outcome in a positive way.
This additional requirement of evidence of improved health outcomes underscores
the importance of patient participation in long-term research in genetic medicine.
Particularly for genetic tests, data on health outcomes may take a very long time to
collect.
Policy Issues. Decisions by insurers to cover new genetic tests have a
significant impact on the utilization of such tests and their eventual integration into
the health care system. The integration of personalized medicine into the health care
system will be significantly affected by coverage decisions. Although insurers are
beginning to cover pharmacogenomic tests and treatments, the high cost of such tests
and treatments often means that insurers require very stringent evidence that they will
improve health outcomes. In addition, the fact that Medicare does not routinely
cover preventive services (unless authorized specifically by Congress) means that
coverage for many genetic tests and services, which may be considered preventive,
may not be granted under Medicare. As Medicare coverage decisions are often
looked to by private insurers as a guide for their own coverage decisions, it is
difficult to predict what effect this might have on the uptake and utilization of genetic
tests more broadly.
Regulation of Genetic Tests by the Federal Government
Genetic tests are regulated by the FDA and CMS through CLIA. FDA regulates
genetic tests that are manufactured by industry and sold for clinical diagnostic use.
These test kits usually come prepackaged with all of the reagents and instructions that
a laboratory needs to perform the test and are considered to be products by the FDA.
FDA requires manufacturers of the kits to make sure that the test detects what they
say it will, in the patient population in which they intend the test to be used. With
respect to the characteristics of a genetic test, this process requires manufacturers to
prove that their test is clinically valid. Depending on the perceived risk associated
with the intended use promoted by the manufacturer, genetic tests must either prove
that they are safe and effective, or that they are substantially equivalent to something
that is already on the market that has the same intended use.
Most genetic tests are performed, not with test kits, but rather as laboratory
testing services (or “homebrew” tests), meaning that clinical laboratories themselves
perform the test in-house and make most or all of the reagents used in the tests.
Homebrew tests are not currently regulated by the FDA in the way kits are and,
therefore, the clinical validity of the vast majority of genetic tests is not regulated.
The FDA does regulate certain components used in homebrew tests, known as
Analyte Specific Reagents (ASRs), if the ASR is commercially available. If the ASR
is made in-house by a laboratory performing a homebrew test, the test is not regulated
at all by the FDA. This type of test is known as a “homebrew-homebrew” test.
Any clinical test that is performed with results returned to the patient must be
performed in a CLIA-certified laboratory. CLIA is primarily administered by CMS
in conjunction with the Centers for Disease Control and Prevention (CDC) and the
FDA.12 FDA determines the category of complexity of the test so that laboratories
know which parts of CLIA they must follow. As previously noted, CLIA regulates
the analytical validity of a clinical laboratory test only. It generally establishes
requirements for laboratory processes, such as personnel training and quality
control/quality assurance programs. CLIA requires laboratories to prove that their
tests work properly, to maintain the appropriate documentation, and to show that tests
are interpreted by laboratory professionals with the appropriate training. However,
CLIA does not require that tests made by laboratories undergo any review by an
outside agency to see if they work properly. Proponents of CLIA argue that
regulation of the testing process gives the laboratories optimal flexibility to modify
tests as new information becomes available. Critics argue that CLIA does not go far
enough to assure the accuracy of genetic tests since it only addresses analytical
validity and not clinical validity.
12 See [http://www.cms.hhs.gov/CLIA/].