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Genetic testing








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Genetic testing, also known as DNA testing, allows the determination of bloodlines and the genetic diagnosis of vulnerabilities to inherited diseases. In agriculture, a form of genetic testing known as progeny testing can be used to evaluate the quality of breeding stock. In population ecology, genetic testing can be used to track genetic strengths and vulnerabilities of species populations.
In humans, genetic testing can be used to determine a child's parentage (genetic mother and father) or in general a person's ancestry or biological relationship between animal people. In addition to studying chromosomes to the level of individual genes, genetic testing in a broader sense includes biochemical tests for the possible presence of genetic diseases, or mutant forms of genes associated with increased risk of developing genetic disorders.
Genetic testing identifies changes in chromosomes, genes, or proteins.[1] The variety of genetic tests has expanded throughout the years. In the past, the main genetic tests searched for abnormal chromosome numbers and mutations that lead to rare, inherited disorders. Today, tests involve analyzing multiple genes to determine the risk of developing specific diseases or disorders, with the more common diseases consisting of heart disease and cancer.[2] The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person's chance of developing or passing on a genetic disorder. Several hundred genetic tests are currently in use, and more are being developed.[3][4]
Because genetic mutations can directly affect the structure of the proteins they code for, testing for specific genetic diseases can also be accomplished by looking at those proteins or their metabolites, or looking at stained or fluorescent chromosomes under a microscope.[5]
Types
Genetic testing is "the analysis of chromosomes (DNA), proteins, and certain metabolites in order to detect heritable disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes."[6] It can provide information about a person's genes and chromosomes throughout life. Available types of testing include:
Cell-free fetal DNA (cffDNA) testing is a non-invasive (for the fetus) test. It is performed on a sample of venous blood from the mother, and can provide information about the fetus early in pregnancy.[7] As of 2015 it is the most sensitive and specific screening test for Down syndrome.[8]
Newborn screening: Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. A blood sample is collected with a heel prick from the newborn 24–48 hours after birth and sent to the lab for analysis. In the United States, newborn screening procedure varies state by state, but all states by law test for at least 21 disorders. If abnormal results are obtained, it does not necessarily mean the child has the disorder. Diagnostic tests must follow the initial screening to confirm the disease.[9] The routine testing of infants for certain disorders is the most widespread use of genetic testing—millions of babies are tested each year in the United States. All states currently test infants for phenylketonuria (a genetic disorder that causes mental illness if left untreated) and congenital hypothyroidism (a disorder of the thyroid gland). People with PKU do not have an enzyme needed to process the amino acid phenylalanine, which is responsible for normal growth in children and normal protein use throughout their lifetime. If there is a buildup of too much phenylalanine, brain tissue can be damaged, causing developmental delay. Newborn screening can detect the presence of PKU, allowing children to be placed on special diets to avoid the effects of the disorder.[9]
Diagnostic testing: Diagnostic testing is used to diagnose or rule out a specific genetic or chromosomal condition. In many cases, genetic testing is used to confirm a diagnosis when a particular condition is suspected based on physical mutations and symptoms. Diagnostic testing can be performed at any time during a person's life, but is not available for all genes or all genetic conditions. The results of a diagnostic test can influence a person's choices about health care and the management of the disease. For example, people with a family history of polycystic kidney disease (PKD) who experience pain or tenderness in their abdomen, blood in their urine, frequent urination, pain in the sides, a urinary tract infection or kidney stones may decide to have their genes tested and the result could confirm the diagnosis of PKD.[10]
Carrier testing: Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder. This type of testing is offered to individuals who have a family history of a genetic disorder and to people in ethnic groups with an increased risk of specific genetic conditions. If both parents are tested, the test can provide information about a couple's risk of having a child with a genetic condition like cystic fibrosis.
Preimplantation genetic diagnosis: Genetic testing procedures that are performed on human embryos prior to the implantation as part of an in vitro fertilization procedure. Pre-implantation testing is used when individuals try to conceive a child through in vitro fertilization. Eggs from the woman and sperm from the man are removed and fertilized outside the body to create multiple embryos. The embryos are individually screened for abnormalities, and the ones without abnormalities are implanted in the uterus.[11]
Prenatal diagnosis: Used to detect changes in a fetus's genes or chromosomes before birth. This type of testing is offered to couples with an increased risk of having a baby with a genetic or chromosomal disorder. In some cases, prenatal testing can lessen a couple's uncertainty or help them decide whether to abort the pregnancy. It cannot identify all possible inherited disorders and birth defects, however. One method of performing a prenatal genetic test involves an amniocentesis, which removes a sample of fluid from the mother’s amniotic sac 15 to 20 or more weeks into pregnancy. The fluid is then tested for chromosomal abnormalities such as Down syndrome (Trisomy 21) and Trisomy 18, which can result in neonatal or fetal death. Test results can be retrieved within 7–14 days after the test is done. This method is 99.4% accurate at detecting and diagnosing fetal chromosome abnormalities. Although there is a risk of miscarriage associated with an amniocentesis, the miscarriage rate is only 1/400. Another method of prenatal testing is Chorionic Villus Sampling (CVS). Chorionic villi are projections from the placenta that carry the same genetic makeup as the baby. During this method of prenatal testing, a sample of chorionic villi is removed from the placenta to be tested. This test is performed 10–13 weeks into pregnancy and results are ready 7–14 days after the test was done.[12] Another test using blood taken from the fetal umbilical cord is percutaneous umbilical cord blood sampling.
Predictive and presymptomatic testing: Predictive and presymptomatic types of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a genetic disorder, but who have no features of the disorder themselves at the time of testing. Predictive testing can identify mutations that increase a person's chances of developing disorders with a genetic basis, such as certain types of cancer. For example, an individual with a mutation in BRCA1 has a 65% cumulative risk of breast cancer.[13] Hereditary breast cancer along with ovarian cancer syndrome are caused by gene alterations in the genes BRCA1 and BRCA2. Major cancer types related to mutations in these genes are female breast cancer, ovarian, prostate, pancreatic, and male breast cancer.[14] Li-Fraumeni syndrome is caused by a gene alteration on the gene TP53. Cancer types associated with a mutation on this gene include breast cancer, soft tissue sarcoma, osteosarcoma (bone cancer), leukemia and brain tumors. In the Cowden syndrome there is a mutation on the PTEN gene, causing potential breast, thyroid or endometrial cancer.[14] Presymptomatic testing can determine whether a person will develop a genetic disorder, such as hemochromatosis (an iron overload disorder), before any signs or symptoms appear. The results of predictive and presymptomatic testing can provide information about a person’s risk of developing a specific disorder, help with making decisions about medical care and provide a better prognosis.
Pharmacogenomics: type of genetic testing that determines the influence of genetic variation on drug response. When a person has a disease or health condition, pharmacogenomics can examine an individual’s genetic makeup to determine what medicine and what dosage would be the safest and most beneficial to the patient. In the human population, there are approximately 11 million single nucleotide polymorphisms (SNPs) in people’s genomes, making them the most common variations in the human genome. SNPs reveal information about an individual’s response to certain drugs. This type of genetic testing can be used for cancer patients undergoing chemotherapy.[15] A sample of the cancer tissue can be sent in for genetic analysis by a specialized lab. After analysis, information retrieved can identify mutations in the tumor which can be used to determine the best treatment option.[16]
Non-diagnostic testing includes:
Forensic testing: Forensic testing uses DNA sequences to identify an individual for legal purposes. Unlike the tests described above, forensic testing is not used to detect gene mutations associated with disease. This type of testing can identify crime or catastrophe victims, rule out or implicate a crime suspect, or establish biological relationships between people (for example, paternity).
Paternity testing: This type of genetic test uses special DNA markers to identify the same or similar inheritance patterns between related individuals. Based on the fact that we all inherit half of our DNA from the father, and half from the mother, DNA scientists test individuals to find the match of DNA sequences at some highly differential markers to draw the conclusion of relatedness.
Genealogical DNA test: To determine ancestry or ethnic heritage for genetic genealogy
Research testing: Research testing includes finding unknown genes, learning how genes work and advancing our understanding of genetic conditions. The results of testing done as part of a research study are usually not available to patients or their healthcare providers.
Specific diseases


Many diseases have a genetic component with tests already available. This list is continuously changing with additions of new test availabilities. This list below is just a few of the thousands of tests available.
African iron overload
Over-absorption of iron; accumulation of iron in vital organs (heart, liver, pancreas); organ damage; heart disease; cancer; liver disease; arthritis; diabetes; infertility; impotence[17]
Alpha-1 antitrypsin deficiency
Obstructive lung disease in adults; liver cirrhosis during childhood; when a newborn or infant has jaundice that lasts for an extended period of time (more than a week or two), an enlarged spleen, ascites (fluid accumulation in the abdominal cavity), pruritus (itching), and other signs of liver injury; persons under 40 years of age that develops wheezing, a chronic cough or bronchitis, is short of breath after exertion and/or shows other signs of emphysema (especially when the patient is not a smoker, has not been exposed to known lung irritants, and when the lung damage appears to be located low in the lungs); when you have a close relative with alpha-1 antitrypsin deficiency; when a patient has a decreased level of A1AT.
Apolipoprotein E-associated
Elevation of both serum cholesterol and triglycerides; accelerated atherosclerosis, coronary heart disease; cutaneous xanthomas; peripheral vascular disease; diabetes mellitus, obesity or hypothyroidism. The APOE gene is also related to the development of complex genetic disorders like Alzheimer's disease.
Becker/Duchenne muscular dystrophy
Muscle weakness (rapidly progressive); frequent falls; difficulty with motor skills (running, hopping, jumping); progressive difficulty walking (ability to walk may be lost by age 12); fatigue; intellectual retardation (possible); skeletal deformities; chest and back (scoliosis); muscle deformities (contractures of heels, legs; pseudohypertrophy of calf muscles)
Beta-thalassemia
Reduced synthesis of the hemoglobin-beta chain; microcytic hypochromic anemia[18]
Factor II
Venous thrombosis; certain arterial thrombotic conditions; patients with deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, and premature ischemic stroke and also of women with premature myocardial infarction; family history of early onset stroke, deep vein thrombosis, thromboembolism, pregnancy associated with thrombosis/embolism, hyperhomocysteinemia, and multiple miscarriage. Individuals with the mutation are at increased risk of thrombosis in the setting of oral contraceptive use, trauma, and surgery.
Factor V Leiden
Venous thrombosis; pulmonary embolism; transient ischemic attack or premature stroke; peripheral vascular disease, particularly lower extremity; occlusive disease; cerebral vein thrombosis; multiple spontaneous abortions; intrauterine fetal demise
Homocysteine
Venous thrombosis; increased plasma homocysteine levels
PAI-1 gene mutation
Independent risk factor for coronary artery disease, ischemic stroke, venous thrombosis (including osteonecrosis)
Breast, ovarian and prostate cancer
Uncontrolled division of cancer cells
Crohn's disease
Inflammation confined to the colon; abdominal pain and bloody diarrhea; anal fistulae and peri-rectal abscesses can also occur
Cystic fibrosis
Large amount of abnormally thick mucus in the lungs and intestines; leads to congestioni, pneumonia, diarrhea and poor growth
Deafness (non-syndromic)
Congenital loss of hearing; -prelingual, non-syndromic deafness
Familial hypercholesterolemia
Tendon xanthomas; elevated LDL cholesterol; premature heart disease
Fanconi anaemia
Predisposition of acute myeloid leukemia; skeletal abnormalities; radial hypoplasia and vertebral defect and other physical abnormalities, bone marrow failure (pancytopenia), endocrine dysfunction, early onset osteopenia/osteoporosis and lipid abnormalities, spontaneous chromosomal breakage exacerbated by exposure to DNA cross-linking agents.
Fragile-X syndrome
Mental retardation or learning disabilities of unknown etiology; autism or autistic-like characteristics; women with premature menopause.
Subtle dysmorphism, log face with prominent mandible and large ears, macroorchidism in postpubertal males, behavioral abnormalities, due to lack of FMR1 in areas such as the cerebral cortex, amygdala, hippocampus and cerebellum
Friedreich's ataxia
Characterized by slowly progressive ataxia; typically associated with depressed tendon reflexes, dysarthria, Babinski responses, and loss of position and vibration senses
Hereditary hemochromatosis[19]
Over-absorption of iron; accumulation of iron in vital organs (heart, liver, pancreas); organ damage; heart disease; cancer; liver disease; arthritis; diabetes; infertility; impotence
Hirschsprung's disease
Absence of ganglia in the gut
Huntington disease
Progressive disorder of motor, cognitive, and psychiatric disturbances.
Lactose Intolerance
Hypolactasia; persistent diarrhea; abdominal cramps; bloating; nausea; flatus
Multiple endocrine neoplasia
MEN2A (which affects 60% to 90% of MEN2 families):Medullary thyroid carcinoma; Pheochromocytoma (tumor of the adrenal glands); Parathyroid adenomas (benign [noncancerous] tumors) or hyperplasia (increased size) of the parathyroid gland; MEN2B (which affects 5% of MEN2 families): Medullary thyroid carcinoma; Pheochromocytoma; Mucosal neuromas (benign tumors of nerve tissue on the tongue and lips); Digestive problems; Muscle, joint, and spinal problems; Typical facial features; Familial medullary thyroid carcinoma (FMTC) (which affects 5% to 35% of MEN2 families):Medullary thyroid carcinoma only
Myotonic muscular dystrophy
Affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system; clinical findings, which span a continuum from mild to severe, have been categorized into three somewhat overlapping phenotypes: mild, classic, and congenital.
Pseudocholinesterase deficiency
Pseudocholinesterase (also called butyrylcholinesterase or "BCHE") hydrolyzes a number of choline-based compounds including cocaine, heroin, procaine, and succinylcholine, mivacurium, and other fast-acting muscle relaxants.[20] Mutations in the BCHE gene lead to deficiency in the amount or function of the protein, which in turn results in a delay in the metabolism of these compounds, which prolongs their effects. Succinylcholine is commonly used as an anaesthetic in surgical procedures, and a person with BCHE mutations may suffer prolonged paraylasis. Between 1 in 3200 and 1 in 5000 people carry BCHE mutations; they are most prevalent in Persian Jews and Alaska Natives.[20][21] As of 2013 there are 9 genetic tests available.[22]
Sickle cell anaemia
Variable degrees of hemolysis and intermittent episodes of vascular occlusion resulting in tissue ischemia and acute and chronic organ dysfunction; complications include anemia, jaundice, predisposition to aplastic crisis, sepsis, cholelithiasis, and delayed growth. Diagnosis suspected in infants or young children with painful swelling of the hands and feet, pallor, jaundice, pneumococcal sepsis or meningitis, severe anemia with splenic enlargement, or acute chest syndrome.
Tay–Sachs disease
Lipids accumulate in the brain; neurological dysfunction; progressive weakness and loss of motor skills; decreased social interaction, seizures, blindness, and total debilitation
Variegate porphyria
Cutaneous photosensitivity; acute neurovisceral crises
Medical procedure
Genetic testing is often done as part of a genetic consultation and as of mid-2008 there were more than 1,200 clinically applicable genetic tests available.[23] Once a person decides to proceed with genetic testing, a medical geneticist, genetic counselor, primary care doctor, or specialist can order the test after obtaining informed consent.
Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue. For example, a medical procedure called a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside surface of the cheek. Alternatively, a small amount of saline mouthwash may be swished in the mouth to collect the cells. The sample is sent to a laboratory where technicians look for specific changes in chromosomes, DNA, or proteins, depending on the suspected disorders, often using DNA sequencing. The laboratory reports the test results in writing to a person's doctor or genetic counselor.
Routine newborn screening tests are done on a small blood sample obtained by pricking the baby's heel with a lancet.
Risks and limitations
The physical risks associated with most genetic tests are very small, particularly for those tests that require only a blood sample or buccal smear (a procedure that samples cells from the inside surface of the cheek). The procedures used for prenatal testing carry a small but non-negligible risk of losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or tissue from around the fetus.[24]
Many of the risks associated with genetic testing involve the emotional, social, or financial consequences of the test results. People may feel angry, depressed, anxious, or guilty about their results. The potential negative impact of genetic testing has led to an increasing recognition of a "right not to know".[25] In some cases, genetic testing creates tension within a family because the results can reveal information about other family members in addition to the person who is tested.[26] The possibility of genetic discrimination in employment or insurance is also a concern. Some individuals avoid genetic testing out of fear it will affect their ability to purchase insurance or find a job.[27] Health insurers do not currently require applicants for coverage to undergo genetic testing, and when insurers encounter genetic information, it is subject to the same confidentiality protections as any other sensitive health information.[28] In the United States, the use of genetic information is governed by the Genetic Information Nondiscrimination Act (GINA) (see discussion below in the section on government regulation).
Genetic testing can provide only limited information about an inherited condition. The test often can't determine if a person will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. Another major limitation is the lack of treatment strategies for many genetic disorders once they are diagnosed.[24]
Another limitation to genetic testing for a hereditary linked cancer, is the variants of unknown clinical significance. Because the human genome has over 22,000 genes, there are 3.5 million variants in the average person's genome. These variants of unknown clinical significance means there is a change in the DNA sequence, however the increase for cancer is unclear because it is unknown if the change affects the gene's function.[29]
A genetics professional can explain in detail the benefits, risks, and limitations of a particular test. It is important that any person who is considering genetic testing understand and weigh these factors before making a decision.[24]
Other risks include accidental findings—a discovery of some possible problem found while looking for something else.[30] In 2013 the American College of Medical Genetics and Genomics (ACMG) that certain genes always be included any time a genomic sequencing was done, and that labs should report the results.[31]
Direct-to-consumer genetic testing
Direct-to-consumer (DTC) genetic testing is a type of genetic test that is accessible directly to the consumer without having to go through a health care professional. Usually, to obtain a genetic test, health care professionals (such as doctors) acquire their patient's permission and then order the desired test. DTC genetic tests, however, allow consumers to bypass this process and order DNA tests themselves.
There is a variety of DTC tests, ranging from tests for breast cancer alleles to mutations linked to cystic fibrosis. Benefits of DTC testing are the accessibility of tests to consumers, promotion of proactive healthcare, and the privacy of genetic information. Possible additional risks of DTC testing are the lack of governmental regulation, the potential misinterpretation of genetic information, issues related to testing minors, privacy of data, and downstream expenses for the public health care system.[32]
Controversy
DTC genetic testing has been controversial due to outspoken opposition within the medical community. Critics of DTC testing argue against the risks involved, the unregulated advertising and marketing claims, and the overall lack of governmental oversight.[33][34]
DTC testing involves many of the same risks associated with any genetic test. One of the more obvious and dangerous of these is the possibility of misreading of test results. Without professional guidance, consumers can potentially misinterpret genetic information, causing them to be deluded about their personal health.
Some advertising for DTC genetic testing has been criticized as conveying an exaggerated and inaccurate message about the connection between genetic information and disease risk, utilizing emotions as a selling factor. An advertisement for a BRCA-predictive genetic test for breast cancer stated: “There is no stronger antidote for fear than information.”[35]
Ancestry.com, a company providing DTC DNA tests for genealogy purposes, has reportedly allowed the warrantless search of their database by police investigating a murder.[36] The warrantless search led to a search warrant to force the gathering of a DNA sample from a New Orleans filmmaker; however he turned out not to be a match for the suspected killer.[37]
Government regulation in the United States

Currently, the U.S. has no strong federal regulation moderating the DTC market. Though there are several hundred tests available, only a handful are approved by the Food and Drug Administration (FDA); these are sold as at-home test kits, and are therefore considered "medical devices" over which the FDA may assert jurisdiction. Other types of DTC tests require customers to mail in DNA samples for testing; it is difficult for the FDA to exercise jurisdiction over these types of tests, because the actual testing is completed in the laboratories of providers. As of 2007, the FDA had not yet officially substantiated with scientific evidence the claimed accuracy of the majority of direct-to-consumer genetic tests.[38]
With regard to genetic testing and information in general, legislation in the United States called the Genetic Information Nondiscrimination Act prohibits group health plans and health insurers from denying coverage to a healthy individual or charging that person higher premiums based solely on a genetic predisposition to developing a disease in the future. The legislation also bars employers from using individuals’ genetic information when making hiring, firing, job placement, or promotion decisions.[39] The legislation, the first of its kind in the U.S.,[40] was passed by the United States Senate on April 24, 2008, on a vote of 95-0, and was signed into law by President George W. Bush on May 21, 2008.[41][42] It went into effect on November 21, 2009.
In June 2013 the US Supreme Court issued two rulings on human genetics. The Court struck down patents on human genes, opening up competition in the field of genetic testing.[43] The Supreme Court also ruled that police were allowed to collect DNA from people arrested for serious offenses.[44]
In popular culture
Some possible future ethical problems of genetic testing were considered in the science fiction film Gattaca, the novel Next, and the science fiction anime series "Gundam Seed". Also, some films which include the topic of genetic testing include The Island, Halloween: The Curse of Michael Myers, and the Resident Evil series.
Ethics
Pediatric genetic testing
The American Academy of Pediatrics (AAP) and the American College of Medical Genetics (ACMG) have provided new guidelines for the ethical issue of pediatrics genetic testing and screening of children in the United States.[45][46]  Their guidelines state that performing pediatric genetic testing should be in the best interest of the child. In hypothetical situations for adults getting genetically tested 84-98% expressing interest in getting genetically tested for cancer predisposition.[47]  Though only half who are at risk of would get tested. AAP and ACMG recommend holding off on genetic testing for late-onset conditions until adulthood. Unless diagnosing genetic disorders during childhood and start early intervention can reduce morbidity or mortality. They also state that with parents or guardians permission testing for asymptomatic children who are at risk of childhood onset conditions are ideal reasons for pediatrics genetic testing. Testing for pharmacogenetics and newborn screening is found to be acceptable by AAP and ACMG guidelines. 
Histocompatibility testing guideline states that it’s permissible for children of all ages to have tissue compatibility testing for immediate family members but only after the psychosocial, emotional and physical implications has been explored. With a donor advocate or similar mechanism should be in place to protect the minors from coercion and to safeguard the interest of said minor. 
Both AAP and ACMG discourage the use of direct-to-consumer and home kit genetic because of the accuracy, interpretation and oversight of test content. 
Guidelines also state that if parents or guardians should be encouraged to inform their child of the results from the genetic test if the minor is of appropriate age. If minor is of mature appropriate age and request results, the request should be honored. Though for ethical and legal reasons health care providers should be cautions in providing minors with predictive genetic testing without the involvement of parents or guardians. Within the guidelines AAP and ACMG state that health care provider have an obligation to inform parents or guardians on the implication of test results. To encourage patients and families to share information and even offer help in explain results to extend family or refer them to genetic counseling. 
AAP and ACMG state any type of predictive genetic testing for all types is best offer with genetic counseling being offer by Clinical genetics, genetic counselors or health care providers.[46]
Israel
Israel uses DNA testing to determine if people are eligible for immigration. The policy where "many Jews from the Former Soviet Union (‘FSU’) are asked to provide DNA confirmation of their Jewish heritage in the form of paternity tests in order to immigrate as Jews and become citizens under Israel's Law of Return" has generated controversy.[48][49][50][51]
Costs
The cost of genetic testing can range from under $100 to more than $2,000. This depends on the complexity of the test. The cost will increase if more than one test is necessary or if multiple family members are getting tested to obtain additional results. Costs can vary by state and some states cover part of the total cost.
From the date that a sample is taken, results may take weeks to months, depending upon the complexity and extent of the tests being performed. Results for prenatal testing are usually available more quickly because time is an important consideration in making decisions about a pregnancy. Prior to the testing, the doctor or genetic counselor who is requesting a particular test can provide specific information about the cost and time frame associated with that test.[52]
See also

DNA profiling
Genographic Project
Personalized medicine
Elective genetic and genomic testing
Eugenics
Full Genome Sequencing
Whole Genome Sequencing
Whole Exome Sequencing
Genetic counseling
List of genetic disorders
List of genetic genealogy topics
Non-paternity event


This article incorporatespublic domain material from the United States Department of Health and Human Servicesdocument .
This article incorporatespublic domain material from the United States Department of Health and Human Servicesdocument .
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