Jeffrey R. Botkin

Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents

In 1995, the American Society of Human Genetics (ASHG) and American College of Medical Genetics and Genomics (ACMG) jointly published a statement on genetic testing in children and adolescents. In the past 20 years, much has changed in the field of genetics, including the development of powerful new technologies, new data from genetic research on children and adolescents, and substantial clinical experience. This statement represents current opinion by the ASHG on the ethical, legal, and social issues concerning genetic testing in children. These recommendations are relevant to families, clinicians, and investigators. After a brief review of the 1995 statement and major changes in genetic technologies in recent years, this statement offers points to consider on a broad range of test technologies and their applications in clinical medicine and research. Recommendations are also made for record and communication issues in this domain and for professional education.

Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives

Summary of Recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer to reduce morbidity and mortality in relatives. We found insufficient evidence to recommend a specific genetic testing strategy among the several examined.Rationale: Genetic testing to detect Lynch syndrome in individuals with newly diagnosed colorectal cancer (CRC) is proposed as a strategy to reduce CRC morbidity and mortality in their relatives (see Clinical Considerations section for definition of Lynch syndrome). The EGAPP Working Group (EWG) constructed a chain of evidence that linked genetic testing for Lynch syndrome in patients with newly diagnosed CRC with improved health outcomes in their relatives. We found that assessing patients who have newly diagnosed CRC with a series of genetic tests could lead to the identification of Lynch syndrome. Relatives of patients with Lynch syndrome could then be offered genetic testing, and, where indicated, colorectal, and possibly endometrial, cancer surveillance, with the expectation of improved health outcome. The EWG concluded that there is moderate certainty that such a testing strategy would provide moderate population benefit.Analytic Validity: The EWG found adequate evidence to conclude that the analytic sensitivity and specificity for preliminary and diagnostic tests were high.Clinical Validity: After accounting for the specific technologies and numbers of markers used, the EWG found at least adequate evidence to describe the clinical sensitivity and specificity for three preliminary tests, and for four selected testing strategies. These measures of clinical validity varied with each test and each strategy (see Clinical Considerations section).Clinical Utility: The EWG found adequate evidence for testing uptake rates, adherence to recommended surveillance activities, number of relatives approachable, harms associated with additional follow-up, and effectiveness of routine colonoscopy. This chain of evidence supported the use of genetic testing strategies to reduce morbidity/mortality in relatives with Lynch syndrome. Several genetic testing strategies were potentially effective, but none was clearly superior. The evidence for or against effectiveness of identifying mismatch repair (MMR) gene mutations in reducing endometrial cancer morbidity or mortality was inadequate.Contextual Issues: CRC is a common disease responsible for an estimated 52,000 deaths in the United States in 2007. In about 3% of newly diagnosed CRC, the underlying cause is a mutation in a MMR gene (Lynch syndrome) that can be reliably identified with existing laboratory tests. Relatives inheriting the mutation have a high (about 45% by age 70) risk of developing CRC. Evidence suggests these relatives will often accept testing and increased surveillance.

PSYCHOLOGICAL RESPONSES TO BRCA1 MUTATION TESTING: PRELIMINARY FINDINGS

The short-term psychological responses of 60 adult women tested for a BRCA1 gene mutation associated with a high risk of breast and ovarian cancer were investigated. Participants were members of a large kindred enrolled in an ongoing prospective study of the psychosocial impact of genetic testing. Initial results from participants who completed both the pretest baseline and the 1-2 week posttest follow-up interviews are reported. Gene mutation carriers manifested significantly higher levels of test-related psychological distress, as measured by the Impact of Event Scale, when compared with noncarriers. The highest levels of test-related distress were observed among mutation carriers with no history of cancer or cancer-related surgery. Although general distress (state anxiety) declined after testing, carriers were more distressed than noncarriers at follow-up.

Recommendations for Returning Genomic Incidental Findings? We Need to Talk!

The American College of Medical Genetics and Genomics recently issued recommendations for reporting incidental findings from clinical whole-genome sequencing and whole-exome sequencing. The recommendations call for evaluating a specific set of genes as part of all whole-genome sequencing/whole-exome sequencing and reporting all pathogenic variants irrespective of patient age. The genes are associated with highly penetrant disorders for which treatment or prevention is available. The effort to generate a list of genes with actionable findings is commendable, but the recommendations raise several concerns. They constitute a call for opportunistic screening, through intentional effort to identify pathogenic variants in specified genes unrelated to the clinical concern that prompted testing. Yet for most of the genes, we lack evidence about the predictive value of testing, genotype penetrance, spectrum of phenotypes, and efficacy of interventions in unselected populations. Furthermore, the recommendations do not allow patients to decline the additional findings, a position inconsistent with established norms. Finally, the recommendation to return adult-onset disease findings when children are tested is inconsistent with current professional consensus, including other policy statements of the American College of Medical Genetics and Genomics. Instead of premature practice recommendations, we call for robust dialogue among stakeholders to define a pathway to normatively sound, evidence-based guidelines.Genet Med 15 11, 854–859.Genetics in Medicine (2013); 15 11, 854–859. doi:10.1038/gim.2013.113

Genetic testing for a BRCA1 mutation: Prophylactic surgery and screening behavior in women 2 years post testing

Mutations in the BRCA1 gene are associated with an increased risk of breast and ovarian cancer in carrier women. An understanding of behavioral responses to BRCA1 mutation testing by mutation carriers and non‐carriers is important to guide the clinical application of this new technology. This study examined the utilization of genetic testing for a BRCA1 mutation in high‐risk individuals and the response of tested women with respect to interventions for early cancer detection and prevention. This study assessed the utilization of genetic testing for both men and women in a large kindred and the behavioral responses by women with respect to use of health care interventions during the 2 years following testing. Participants were offered BRCA1 mutation testing. Surveillance behaviors related to breast and ovarian cancer were assessed by computer‐assisted telephone interviews at baseline (prior to genetic counseling and testing), 1–2 weeks, 4–6 months, 1 and 2 years after the provision of test results. Mutation carriers, non‐carriers, and individuals of unknown mutation status were compared to determine the impact of test results. Utilization of genetic testing for both men and women are reported and, for women, mammography, breast self‐exam, clinical breast exam, mastectomy, oophorectomy, transvaginal ultrasound, and CA125 screening were assessed. Of those fully informed of the opportunity for testing, 55% of the women and 52% of the men pursued genetic testing. With respect to mammography for women 40 years and older, 82% of mutation carriers obtained a mammogram in each year following testing compared to 72% of non‐carrier women the first year and 67% the second year. This mammography utilization represents a significant increase over baseline for both mutation carriers and non‐carriers. Younger carrier women also significantly increased their mammography utilization from baseline. Overall, 29% of the carrier women did not obtain a single mammogram by 2 years post‐testing. At 2 years, 83% of the carrier women and 74% of the non‐carriers reported adherence to recommendations for breast self‐exam and over 80% of carrier women had obtained a clinical breast examination each year following testing. None of the carrier women had obtained a prophylactic mastectomy by 2 years after testing, although 11% were considering this procedure. Of carrier women 25 years of age and older who had at least one intact ovary at the time of testing, 46% of carriers had obtained an oophorectomy 2 years after testing, including 78% of women 40 years of age and older. The majority of carrier women (73%) had discussed their genetic test results with a medical doctor or health care provider. Our results indicate utilization of genetic testing by a majority of high‐risk individuals who received information about testing. Both carriers and non‐carriers increased their utilization of mammography and breast self‐exam following testing. Oophorectomy was obtained by a large proportion of carrier women in contrast to mastectomy which was not utilized within the first 2 years following testing.

Genetic exceptionalism in medicine: Clarifying the differences between genetic and nongenetic tests

The identification of disease-conferring genes and the development of tests to confirm or predict genetic predisposition to disease have been greeted with enthusiasm by the scientific community, but numerous ethical problems related to testing have been identified (15). Some suggest that genetic testing for susceptibility to diseases such as breast cancer is like any other evaluation of asymptomatic persons and should be handled no differently from cholesterol testing (6). This point of view is not widely held, however. Others have recommended treating genetic tests as special by requiring rules to protect privacy, by providing elaborate pretest education and psychological counseling, and by obtaining meaningful informed consent before genetic testing is performed (711). Some have argued that certain genetic tests should be offered only in experimental protocols (7, 12, 13). Legislators have passed laws to limit or prohibit discriminatory uses of genetic information (14), and an advisory committee to the U.S. Surgeon General has recommended that governmental agencies oversee all genetic testing (15). Because genetic testing is already clinically available for several conditions and because such tests will proliferate, clinicians need to know whether to treat genetic tests differently from the nongenetic tests they perform for asymptomatic patients. In this paper, we argue that genetic and nongenetic predictive tests have several common characteristics and address whether these two types of tests have fundamental differences. Genetic tests are currently used in a variety of ways: to confirm a suspected diagnosis, such as the fragile X syndrome in a developmentally delayed child (16, 17); for heterozygote carrier testing, such as in carriers of sickle cell trait (18); for prenatal or preimplantation diagnosis of diseases like Duchenne muscular dystrophy or Down syndrome (19); to screen newborns for such diseases as cystic fibrosis or phenylketonuria (20, 21); or to predict predisposition to late-onset disease, such as breast or colon cancer (2226) or Alzheimer disease (27, 28). Although some imprecision and overlap occur among these categories (29), these distinctions help differentiate various clinical uses of genetic tests. In this paper, we discuss predictive genetic testing, that is, testing of asymptomatic persons for future health problems. Sometimes known as susceptibility testing, this practice often raises particularly troubling ethical concerns (30, 31). In predictive genetic testing, genetic material is analyzed to identify particular mutations or polymorphisms that increase the probability of disease development. Predictive testing differs from diagnostic testing in that the former is generally used to identify risks in those without symptoms, whereas the latter is used to confirm diagnoses in those who are ill. Common Factors among Genetic and Nongenetic Predictive Tests Predictive genetic tests have at least three features in common with nongenetic predictive tests. First, each has a similar main purpose: to identify those at increased risk for developing a health-related disorder later in life (for example, BRCA1/BRCA2 testing to identify risk for breast cancer or cholesterol evaluation to identify risk for heart attack or stoke). Second, the clinical process for obtaining genetic and nongenetic predictive information is often similar. A patient and physician address health maintenance or discuss a health concern, and a history and physical examination are conducted. Ideally, the physician determines whether additional information is needed, mentions the availability of a test to the patient, and discusses the risks and benefits of testing. If the patient decides to be tested, there is little physical risk other than that involved in a simple blood draw or cheek swab. Third, storage and retrieval of results of genetic and nongenetic tests are the same, in the written or computerized medical record (32). All of the advantages and disadvantages of medical record keeping, including lapses of privacy, apply equally to genetic and nongenetic information (3336). Thus, genetic and nongenetic tests have several features in common. To understand the rationale for approaching genetic information with special care, it is necessary to examine arguments about the purportedly unique features of this information. Do Genetic Predictive Tests Warrant Exceptional Treatment? The claim that genetic information is unique and deserves special consideration is known as genetic exceptionalism [37]. There are several reasons why one might be tempted to treat genetic information, particularly that gathered through predictive genetic tests, as exceptional: 1) It can help predict a persons medical future, 2) it divulges information about family members, 3) it has been used to discriminate and stigmatize, and 4) it may result in serious psychological harm (3739). Such reasons have not been universally persuasive, however (37, 40, 41), and a more detailed evaluation shows that there are few, if any, morally relevant differences between genetic and nongenetic tests. We examine each of the preceding four claims in turn. Claim 1: Genetic Information Can Predict a Persons Medical Future One defining characteristic of genetic testing is that it uses molecular information to draw conclusions about a persons past, present, and future health. Susan Vance, whose mother, aunt, two cousins, and two sisters had breast cancer (42), learned, just before surgery to remove both breasts, that she did not carry the mutated gene that ran in her family. Knowledge of her genetic makeup led to cancellation of surgery, a life-altering event. However, the ability to alter lives by predicting future health is not unique to genetic testing. A positive result on an HIV test portends the development of AIDS, a positive result on a tuberculin skin test may foretell the development of active tuberculosis, and high blood pressure or cholesterol measurements may indicate an increased risk for heart disease. Each of these revelations can be life altering. As such, the mere fact that genetic information is predictive does not distinguish it from nongenetic information. There are, however, two important differences between the predictive capabilities of genetic and nongenetic tests. First, although both can identify risk factors for future illness, detection of highly penetrant genetic mutations may indicate a substantially higher risk than abnormalities discovered by nongenetic tests. For instance, persons with genetic mutations for Huntington disease or familial adenomatous polyposis are nearly certain to develop Huntington disease or colon cancer. So, while the type of information delivered by both genetic and nongenetic tests may be similar, for some positive genetic test results the risks detected are greater and disease is inevitable. The second difference is one of perception. Our society views genetic information as somehow more central to our core being than other types of biological information. Right or wrong, genetic information is believed to reveal who we really are, so information from genetic testing is often seen as more consequential than that from other sources (43). Claim 2: Genetic Test Results Divulge Information about Family Members Another feature of predictive genetic testing is that results can affect a patients family. If a woman inherits a mutation in a BRCA1/BRCA2 gene, her risk for breast or ovarian cancer is markedly increased, as is that of her female siblings and children. Likewise, a gene mutation for susceptibility to colon cancer has implications for relatives: Should they be tested? Is there an obligation to disclose test results to relatives who may be affected? Important as it may be, an impact on family members is not unique to predictive genetic testing. As Murray points out (37), a positive result on a tuberculin skin test would certainly affect ones family. If an asymptomatic woman learns during a routine Papanicolaou smear that she has gonorrhea, that too would have implications for her spouse, raising issues about disclosure and confidentiality. What is different between genetic and nongenetic predictive tests is that genetic tests identify predispositions that are exclusively transmitted vertically (from parent to child), while nongenetic tests identify predispositions transmitted in a variety of ways (exposure to common environmental risk factors or person-to-person contact). Thus, through genetic information, a definitive diagnosis can sometimes be made even in a patient who declines to be tested. For example, if a grandparent and grandchild carry the relevant mutation for Huntington disease, the parent between these generations also carries the faulty gene and will almost certainly develop the disease. Claim 3: Genetic Information Can Be Used To Discriminate against and Stigmatize Individuals Historically, genetic information has been used to discriminate against individuals and groups (4446), particularly Jewish persons and other minorities (47). In the early 1900s, bolstered by a popular eugenics movement supported by prominent intellectuals, politicians, and scientists (45, 48), such discriminatory practices were common in the United States. There is considerable concern that the proliferation of new genetic tests could once more lead to unfair or restrictive practices (4953). Several studies have documented discrimination by insurers and employers (5457), although a recent review concluded that actual discrimination by health insurers is rare (58). Despite state and federal legislation to limit or prohibit genetic discrimination in the United States (14, 40, 59, 60), recent rulings in the United Kingdom permit insurers to consider genetic test results when issuing policies (61), and fear of genetic discrimination in the United States has been cited as one of the greatest barriers to the integration of g

National Institutes of Health State-of-the-Science Conference Statement: Family History and Improving Health

The role of obtaining family history information in the primary care setting, the validity of such information, and whether the information affects health outcomes must be clarified. Accordingly, t...

Recommendations from the EGAPP Working Group: testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors

This statement summarizes the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group recommendations regarding CYP450 genetic testing in adult patients beginning treatment with selective serotonin reuptake inhibitors (SSRIs), and the supporting scientific evidence. EGAPP is a project developed by the National Office of Public Health Genomics at the Centers for Disease Control and Prevention to support a rigorous, evidence-based process for evaluating genetic tests and other genomic applications that are in transition from research to clinical and public health practice in the United States. A key goal of the EGAPP Working Group is to develop conclusions and recommendations regarding clinical genomic applications and to establish clear linkage to the supporting scientific evidence. The Working Group members are nonfederal experts in genetics, laboratory medicine, and clinical epidemiology convened to establish methods and processes; set priorities for review topics; participate in technical expert panels for commissioned evidence reviews; publish recommendations; and provide guidance and feedback on other project activities.Summary of Recommendation The EGAPP Working Group found insufficient evidence to support a recommendation for or against use of CYP450 testing in adults beginning SSRI treatment for non-psychotic depression. In the absence of supporting evidence, and with consideration of other contextual issues, EGAPP discourages use of CYP450 testing for patients beginning SSRI treatment until further clinical trials are completed.Rationale: The EGAPP Working Group found no evidence linking testing for CYP450 to clinical outcomes in adults treated with SSRIs. While some studies of a single SSRI dose in healthy patients report an association between genotypic CYP450 drug metabolizer status and circulating SSRI levels, this association was not supported by studies of patients receiving ongoing SSRI treatment. Further, CYP450 genotypes are not consistently associated with the patient outcomes of interest, including clinical response to SSRI treatment or adverse events as a result of treatment. No evidence was available showing that the results of CYP450 testing influenced SSRI choice or dose and improved patient outcomes, or was useful in medical, personal, or public health decision-making. In the absence of evidence supporting clinical utility, it is not known if potential benefits from CYP450 testing will outweigh potential harms. Potential harms may include increased cost without impact on clinical decision making or improvement in patient outcomes, less effective treatment with SSRI drugs, or inappropriate use of genotype information in the management of other drugs metabolized by CYP450 enzymes.

Newborn screening technology: proceed with caution.

The American College of Medical Genetics (ACMG) recommends a significant expansion in the number of conditions targeted by newborn screening (NBS) programs.1 In this commentary we advocate a more cautious approach. NBS dates to the early 1960s, when the technology developed to conduct large-scale testing on dried blood spots for phenylketonuria (PKU).2 PKU remains the paradigm condition for NBS because of features of the disease and its treatment, which are particularly advantageous to population screening. It is a condition that silently causes neurologic devastation but is amenable to early detection and effective prevention with a diet of moderate burden and complexity.3 Many children affected with PKU and their families have benefited from state screening programs over the past 4 decades because of collaboration between health departments, families, primary care providers, and metabolic specialists. However, PKU screening is not an unmitigated success.4,5 There was initial uncertainty about whether children with variant forms of hyperphenylalaninemia required treatment and about whether affected children require life-long dietary management.6 Indeed, some children with benign conditions were seriously harmed from unnecessary restrictions in their diets.5 In addition, long-term studies demonstrate decrements in cognitive function for affected children and adolescents who are not fully adherent to the diet,7,8 yet adherence to the diet is challenging because of its poor palatability, high cost, and limits on insurance coverage in many policies. Affected women who are off the diet are at high risk of bearing severely neurologically impaired children.9 Only recently have many programs begun tracking affected women to enable notification, education, and management. These difficulties by no means negate the value of NBS for PKU, but they highlight the problems with the successful implementation of a population-based screening program even when a model condition is targeted. … Address correspondence to Jeffrey R. Botkin, MD, MPH, Research Administration Building, 75 South 2000 East #108, Salt Lake City, UT 84112-8930. E-mail: jeffrey.botkin{at}hsc.utah.edu

Screening for Sudden Cardiac Death in the Young: Report From a National Heart, Lung, and Blood Institute Working Group

Sudden cardiac death (SCD) in the young (SCDY) has a devastating impact on families, care providers, and the community and attracts significant public and media attention. Sudden cardiac death is defined as an abrupt and unexpected death due to a cardiovascular cause, typically occurring 1 hour from the onset of symptoms. Depending on the source, “young” is variably defined as those less than 25, 30, 35, or 40 years of age. Estimates of the incidence of SCDY (not including infants) vary broadly from 0.6 to 6.2 per 100 000 persons. 1–3 Sudden infant death syndrome (SIDS) may be related to SCD in some infants. Sudden infant death syndrome is defined as the sudden death of an infant 1 year of age that cannot be explained after a thorough investigation is conducted, including an autopsy, death scene evaluation, and review of the clinical history. The incidence of SIDS ranges from 50 to 100 in 100 000,4 and emerging data suggest that as many as 10% to 15% of SIDS deaths are associated with functional cardiac ion channelopathy gene variants.5 The most common diagnoses that increase risk for SCDY include hypertrophic cardiomyopathy (HCM), coronary artery anomalies of wrong sinus origin, myocarditis, arrhythmogenic right ventricular cardiomyopathy, and ion channelopathies.6 The latter category includes hereditary diseases such as the congenital long-QT syndromes (LQTS), catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome, among other less common channelopathies. These diseases are typically undetected before the SCD event. Estimated prevalence rates of these conditions range from 1 per 500 persons for HCM to 1 per 2500 for the LQTS. SCD related to these diagnoses has been documented in infancy and during competitive athletics. In addition, prescription stimulant use for treatment of attention deficit hyperactivity disorder (ADHD) has been postulated to be a trigger for SCD.7,8 Sudden cardiac death in the young is a critical public health issue. A young life cut short represents a devastating event for families, and is associated with many lost productive years. There is significant dissonance among experts in the field about the best approach to prevent SCDY in the United States. Some experts support the implementation of largescale cardiovascular screening programs in infants, in athletes, or in all children to identify at-risk individuals in an effort to prevent SCDY. Cardiovascular screening for SCDY typically involves the addition of an ECG to the current standard of care of history and physical examination. Echocardiography and genetic testing represent alternative or additional screening modalities. Observational data from the Veneto region of Italy suggest that ECG screening can successfully identify at-risk cardiovascular diseases and dramatically reduce the incidence of SCD in competitive athletes.9,10 Proponents of ECG screening in the United States suggest that it can be effective, feasible, and cost-effective. 11 Critics of ECG screening cite a lack of evidence to support its effectiveness or feasibility in the United States; lack of clinical accuracy; cost implications; and the potential clinical, financial, and emotional consequences of falsepositive screening test results. 12 Cost estimates for a national ECG screening program in the United States for