GENETIC TESTING TIME TOOLA Resource from the American College of Preventive Medicine

CLINICAL REFERENCEThe following Clinical Reference Document provides the evidence to support the Genetic Testing Time Tool. The following bookmarks are available to move around the Clinical Reference Document. You may also download a printable version for future reference.

Human genomics, the study of structure, function, and interactions of all genes in the human genome, promises to improve the diagnosis, treatment, and prevention of disease. The proliferation of genetic tests has been greatly accelerated by the Human Genome Project over the last decade. [1]

Meanwhile, practicing physicians and health professionals need to be trained in the principles, applications, and the limitations of genomics and genomic medicine. [2]

Over 1,500 genetic tests are now available clinically, with nearly 300 more available on a research basis only. The number of genetic tests is predicted to increase by 25% annually. [3] There is a boom in the development of genetic tests using the scanning technology from the Genome Project, but questions remain regarding the validity and usefulness of these newer tests.

Genotype: The genetic constitution of the individual; the characterization of the genes. [6]

Phenotype: The observable properties of an individual that are the product of interactions between the genotype and the environment. [6] Nucleotides: The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. [6]

Oligonucleotide: A relatively short single-stranded nucleic-acid chain usually consisting of 2 to 20 nucleotides that is synthesized to match a region where a mutation is known to occur, and then used as a probe. [6]

Single nucleotide polymorphism (SNP): A single nucleotide variation in a genetic sequence that occurs at appreciable frequency in the population. [6]

Penetrance: The probability of developing the disease in those who have the mutation. [6]

Analytic validity: A tests ability to accurately and reliably measure the genotype of interest, and includes measures of analytic sensitivity and specificity, assay robustness, and quality control. [6]

Clinical validity: The ability of the test to accurately and reliably identify or predict the intermediate or final outcomes of interest; usually reported as clinical sensitivity and specificity. [6]

Clinical utility: The balance of benefits and harms associated with the use of a genetic test in practice, including improvement in measureable clinical outcomes and usefulness/added value in clinical management and decision-making compared with not using the test. [6]

Personalized medicine: A rapidly advancing field of healthcare that is informed by each person's unique clinical, genetic (DNA-based), genomic (whole genome or its products), and environmental information. [7]

Genomic medicine: The use of genomic information and its derivatives (RNA, proteins, and metabolites) to guide medical decision making. It is an essential component of personalized medicine. [8]

Genetic tests look for variations in a person's genes or changes in proteins coded for by specific genes. Abnormal results could mean an inherited disorder, or an increased risk for a disease. [1]

Gene tests analyze DNA taken from a person's blood, body fluids or tissues.

Genetic tests can be ordered by a primary care doctor, specialist, medical geneticist, or a genetic counselor with MD oversight. [9]

Acquiring a sample for most tests is simple and low risk-- most require only a sample of blood, hair, or skin. There is higher risk for prenatal testing which requires a sample from the amniotic fluid or chorionic villus during pregnancy. [9]

DNAmicroarrays have many thousands of DNA oligonucleotides to detect SNPs.[9]

Development of Genetic Testing Genetic testing for Mendelian disorders such as cystic fibrosis, Huntington's disease, familial breast cancer, and phenylketonuria, among others, was widely available prior to the genomic era. The genetic basis for complex disease remains unclear. [10]

Association Studies Association studies look for an increased frequency of a particular genotype at a candidate gene locus in cases compared with controls. In these studies, the candidate genes must be known a priori and are therefore limited by understanding of the genes that contribute to a particular disease.

Genetic association studies have been limited by their lack of reproducibility. Even though the contribution of these types of association studies remains uncertain, it has been suggested that common genetic variants may contribute to common diseases, supporting the role for continued association studies. [12]

Single-nucleotide polymorphisms (SNPs) SNPs (pronounced "snips) are the most common type of genetic variation among people. [14]

Each SNP represents a difference in a single DNA building block, called a nucleotide. For example, a SNP may replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a certain stretch of DNA. [14]

SNPs can also influence responses to pharmacotherapy and whether drugs will produce adverse reactions. The development of new drugs can be made far cheaper and more rapid by selecting participants in drug trials based on their genetically determined response to drugs. [15]

Technology Recent advances in molecular technologies have resulted in the ability to screen hundreds of thousands of SNPs and tens of thousands of gene expression profiles. While these data have the potential to inform investigations into disease etiologies and thereby advance medicine, the question of how to adequately control both false positive and false negative rates remains. [16]

Genome Wide Association Studies (GWAS) Genome-wide association studies are a relatively new way for scientists to identify genes involved in human disease. This method searches the genome for single nucleotide polymorphisms (SNPs) in any gene that occur more frequently in people with a particular disease than in people without the disease. [17,18]

Many common diseases, including diabetes mellitus, osteoporosis, and cardiovascular disease, have strong genetic influences but the interactions are complex. [19]

Clinically applicable genetic tests may be used for: [20]

Newborn Screening Newborn screening programs are usually legally mandated and vary from state to state. [21]

In 2005, a federal advisory committee recommended that the number of disorders in state newborn screening programs be expanded from 9 to 29. [22]

Diagnostic Testing [20]

Carrier Testing [20]

Prenatal Testing Offered when there is an increased risk of having a child with a genetic condition due to maternal age, family history, ethnicity, or suggestive multiple marker screen or fetal ultrasound examination. [20]

Preimplantation Testing (Preimplantation Genetic Diagnosis, or PGD) Generally offered to couples with a high chance of having a child with a serious disorder. Preimplantation testing provides an alternative to prenatal diagnosis and termination of affected pregnancies. [20]

Predictive Testing Two types: presymptomatic (eventual development of symptoms is certain when the gene mutation is present, e.g., Huntington disease) and predispositional (eventual development of symptoms is likely but not certain when the gene mutation is present, e.g., breast cancer). [20]

Pharmacogenomic Testing This is another form of testing that is sure to become more common in the future. It involves the study of how genes affect a persons response to drugs -- combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses tailored to a persons genetic makeup. [23]

Within the past decade several pharmacogenetic tests have emerged to aid clinicians in predicting efficacy or toxicity for some drugs. But, knowledge gaps still impede widespread use in the clinical setting. [24]

Examples: Genetic technology has led to some very important therapeutic innovations, including the use of imatinib mesylate (Gleevec) in BCR-ABL chronic myeloid leukemia and of trastuzumab (Herceptin) in Her2-positive breast cancer, but the much anticipated explosion of new effective treatments has been more modest than expected. [26,27]

SSRI response Treatment resistance and intolerance are common with SSRI treatment. [28]

Personalized medicine uses the patient's genetic composition to tailor strategies for patient-specific disease detection, treatment, or prevention. [30]

It promises to use molecular markers to signal the risk of disease or its presence before clinical signs and symptoms appear. [31]

Already having an impact DNA-based risk assessment for common complex disease, molecular signatures for cancer diagnosis and prognosis, and genome-guided therapy and dose selection are important examples for how genome information is already enabling more personalized health care along the continuum from health to disease. [8]

It is also hoped that genetic testing will lead to: [32]

Slow but steady progress The expected transformation toward genomics-based medicine will occur gradually; each new test must be proven, and as proven effective will be incorporated into practice. Currently there are hundreds of tests in the pipeline; some will be found to be useful; many will not. [2]

The ongoing discoveries being made about our genome cause us to question reviews declaring that "personalized medicine is almost here" or that "individualized drug therapy will soon be a reality." [33]

The full application of genomic and personalized medicine in health care will require dramatic changes in regulatory and reimbursement policies as well as legislative protections for privacy for system-wide adoption. [8]

For most diseases, many pieces of the genetic puzzle remain to be discovered, along with how those pieces interact with lifestyle and environmental factors. That means today's tests may falsely reassure people with undiscovered risk factors and needlessly alarm those with undiscovered protective factors. [1]

An important limitation is the lack of a sufficient evidence-based rationale for an association between the genotype and the phenotype. [34]

Genetic cancer screening has been limited to high-risk individuals with a strong hereditary predisposition to cancer. [35]

Genetic testing for susceptibility to common diseases based on a combination of genetic markers may be needed because the effect size associated with each genetic marker is small. [36]

Common diseases such as type 2 diabetes and coronary heart disease result from a complex interplay of genetic and environmental factors. [37]

New gene discoveries from genome-wide association studies will certainly further improve the prediction of common diseases, but it is another question if this improvement will enable personalized medicine. [37]

Although single gene analyses may help elucidate underlying mechanistic pathways, they do not take into account all of the variation in the human genome. [38]

Genome-wide association studies have been limited by the use of thousands of markers when actually hundreds of thousands are required, and by the use of hundreds of individuals when thousands are required.

Technological progress has improved the detection rate in patients with familial hypercholesterolemia.

There are high expectations about the capabilities of pharmacogenetics to tailor psychotropic treatment and "personalize" treatment. [41]

Prospective cohort studies are costly and time consuming but are necessary to show the clinical utility of genetic testing; they are the best means for understanding how genes interact with environmental risk factors to cause disease. [42]

There are two major sources of evidence-based recommendations for genetic testing in the U.S.:

EGAPP was launched to establish a systematic, evidence-based process for evaluating genetic tests and other applications of genomic technology as they are translated from research into clinical practice. [43]

USPSTF Recommendations:

1. BRCA1 and 2 testing for hereditary breast and ovarian cancer. [44]

2. Hemochromatosis [45]

3. Fecal DNA testing for colorectal cancer screening. [46]

EGAPP Recommendations:

1. CYP450 testing for the treatment of depression [48]

2. Lynch Syndrome [49]

3. UGT1A1 genotyping in patients with metastatic colorectal cancer [50]

4. Tumor gene expression profiles for women with early-stage breast cancer [51]

SUMMARY

1. Two tests for which widespread use is recommended:

2. Another test for which use is not recommended:

3. A test for which use is discouraged:

4. Three tests for which evidence is insufficient to make a recommendation:

Evidence Reports: CDC-funded evidence-based reports that guide genomic testing and diagnostic strategies include: [52]

Genetic Testing for Alzheimers Disease: Alzheimers is the object of intense genetic research. Researchers have identified four variants of genes associated with the disease.

The fourth gene, APOE-e4 on chromosome 19, is linked to a greater risk of developing late-onset Alzheimers, the more common form of the disease.

Genetic testing for Alzheimers is not recommended at this time, but, If performed, should be done with pre- and post-test counseling, which includes a full discussion of the implication of the test and all information necessary to make an informed decision. http://www.alz.org/national/documents/topicsheet_genetictesting.pdf

PROS [1,53] People in families at high risk for a genetic disease have to live with uncertainty about their future and their children's future.

Pharmacogenetic testing can help to identify the best medicine or dose of a medicine; can help reduce adverse effects. [1]

The physical risks associated with most genetic tests are very small, particularly if only a blood sample or buccal smear (a procedure that samples cells from the inside surface of the cheek) is required.

CONS Prenatal testing carries a small but real risk of losing the pregnancy (miscarriage) because it requires a sample of amniotic fluid or tissue from around the fetus. [54]

Many of the risks associated with genetic testing involve emotional, social, or financial consequences of the test results. [54]

A serious issue in genetic testing is the "worried well" those who believe their genetic predisposition places them at higher risk than they really are. [55]

The possibility of genetic discrimination in employment or insurance is also a concern, even though there are laws to prevent these practices. [54]

Genetic tests can only provide limited information about an inherited condition; they cannot determine if or when a person will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. [54]

OTHER ISSUES Impact of knowing positive carrier status The impact of carrier status on risk perspectives is not well understood.

Overall, predispositional genetic testing has been shown to have no significant impact on psychological outcomes or changes in perceived risk, and little effect on behavior. [56]

Stigmatization regarding mental disorders An optimistic view is that information on the genetic risk for mental disorders will reduce blame and social stigma in individuals living with mental disorder. [57]

Ethical issues Individuals have a moral obligation to communicate genetic information to their family members. Genetic health professionals should encourage individuals to communicate this information to their family members, and genetic health professionals should support individuals throughout the communication process. [58]

Health care professionals have a duty to inform patients about the potential genetic risks to their relatives. [58a]

Concerns about testing The integration of pharmacogenetic testing into routine care depends upon both patient and physician acceptance of the tests. [59]

Primary care physicians represent the front line of screening for inherited disease risks. [60]

Clinicians need to learn how to read and interpret the results of genetic tests, and to understand when to refer patients to specialists and ask for second opinions and reinterpretation of genetic information. [63]

All health care professionals ought to be prepared to address the complex personal, cultural, theological, ethical, legal, and social issues associated with genetic testing and other genetic issues commonly encountered in clinical practice. [63a]

A qualitative study using focus groups examined family physicians' experiences in dealing with genetic susceptibility to cancer. Participants anticipated an expanding role for family practices in risk assessment, gate-keeping, and ordering genetic tests. They were concerned about the complexity of genetic testing, the lack of evidence regarding management, and the implications for families. [63c]

Patient Needs Patient interest in genetic testing for susceptibility to both heart disease and cancer is high. [63d]

When patients want to make informed decisions about genetic testing, they require genetic knowledge, and they prefer to get this information from their primary care doctor. [64]

Need to allay fears of discrimination Though the US passed the Genetic Information Non-Discrimination Act, many questions remain of how individuals confronting genetic disease view and experience possible discrimination. Discrimination can be implicit, indirect and subtle, rather than explicit, direct and overt; and be hard to prove. Patients may be treated "differently" and unfairly, raising questions of how to define "discrimination", and "appropriate accommodation". [66a]

Read more:

Genetic Testing Clinical Reference For Clinicians ...