Sara Pirzadeh-Miller, MS

The genomic revolution has the potential to change the practice of medicine and healthcare. Advances in technology are driving down the cost of genetic testing, the public is more aware of and interested in such testing and its uses, and genetic testing companies are now offering direct-to-consumer (DTC) testing via kits sold on the Internet. Some argue that these changes make genetic testing more accessible to the general public and medical community at large and that these changes are critical to the full integration of genomic technology into society. However, many of the DTC tests offered are of questionable accuracy and utility and combine tests that provide mundane information about genetic traits with those for serious genetic conditions with life-threatening implications for the patient and the entire family. We will examine both sides of the issues surrounding DTC genetic testing, focusing on important considerations for clinicians using case vignettes to illustrate key issues.

Is DTC testing worthwhile for your patients?

Point: The testing and result interpretations provided are not necessarily clinically accurate or helpful.

Numerous studies have shown that average patients and clinicians are not well versed on even the most basic elements of genetic testing and result interpretation. 1 It is even less likely that consumers and clinicians will understand the subtle differences between DTC companies and tests—particularly genomic profiling based on single nucleotide polymorphisms (SNPs)—which are offered by most DTC companies. The difference between SNPbased testing and clinical single-gene testing with regard to predictive value is a confusing concept that typical consumers and clinicians without adequate training may not understand. For most of the SNP-based genomic profiles offered DTC, there is a lack of consensus among the scientific and medical communities regarding test interpretation.

The positive and negative predictive values, along with the discriminatory accuracy of these tests, are in sharp contrast to those associated with testing for mutations in high-penetrance Mendelian genes. Discriminatory accuracy refers to the ability of a test to determine who will or will not develop the disease or condition and is a balance between sensitivity and specificity. For example, those who test positive for a mutation in the Huntington's disease gene are certain to develop the disease, whereas those who test negative are unlikely to do so. Similarly, in cancer genetics, those with a mutation in the APC gene (causative of familial adenomatous polyposis) will develop colon polyps and colon cancer without appropriate intervention.

With these Mendelian conditions, the relative risk of disease (penetrance) is large (often 10-fold or greater), and the proportion of disease attribestimated by these companies fail to account for known family history or other risk factors. An investigation in July 2010 by the US General Accounting Office concluded that such tests were “misleading and of little or no practical use.”14 The risk profiles provided by such companies have been described as having “no predictive value” and may falsely alarm or reassure consumers.15

Counterpoint: Individuals have the right to explore their own genetic makeup through these emerging tests and may deem testing worthwhile. Some individuals may learn important information they would otherwise not have learned.

One argument to be made is that genetic technology exists and individuals have the right to explore the testing available, regardless of its accuracy and utility. Many DTC sites do state that their testing is intended for entertainment purposes only, although this statement is often in the fine print (see next point). It is possible that DTC testing has made the public more aware of genetic and genomic testing, therefore encouraging the medical profession to keep up with this technology as it pertains to one's area of expertise. Although some may see this as an additional burden on the primary care provider, it can also be viewed as an opportunity to increase awareness and education on the part of both the consumer and the professional. Most current genomic technology was not developed when most of today’s physicians went to medical school, and even most new graduates are not well versed in genetic testing. DTC genetic testing could encourage the medical community to increase its understanding of this new emerging technology.

Although most of the DTC testing offered is of questionable utility, some panels do include important genetic information, like the three common Jewish BRCA mutations. It may be considered ethically questionable to offer testing for hereditary breast cancer and ovarian cancer without full informed consent and adequate result disclosure. However, one can also argue that individuals will gain potentially lifesaving information they might never have uncovered without such testing.

Proponents of DTC genomic profiling suggest that the clinical usefulness of SNP-based testing will improve based on emerging data that analyze the interaction between genetic polymorphisms and environmental factors in predicting disease risk. For example, preliminary studies evaluating SNPs associated with colorectal cancer have found that relative risks are increased when combined with environmental factors, such as high intake of processed meats.16,17 Despite these early findings, it remains to be seen whether the complexity of gene-environment and gene-gene interactions can be elucidated to the extent that will be required to yield highly predictive DTC tests.

Is DTC advertising accurate, fair, and helpful?

Point: DTC advertising overemphasizes the benefits of testing and does not adequately describe the limitations and risks.

Unlike pharmaceutical advertising, which is tightly regulated and requires companies to discuss associated risks, oversight of genetic testing advertisements is limited.18 This can lead to skewing of information that overemphasizes the benefits of genetic testing and does not adequately define the risks and limitations.19,20 One recent study demonstrated that when individuals are provided with accurate information regarding the actual risks and limitations of online DTC genetic testing, they have reduced intentions to obtain such tests and less positive views of Internet-based testing. 19 Furthermore, an investigation of DTC advertising revealed “egregious examples” of deceptive marketing, such as claims that consumers’ DNA could be used to create personalized supplements to cure disease or that results of such DNA tests could be used to predict the athletic potential of their children.14

Many DTC companies have a clause indicating that their testing is intended for research, educational, or entertainment purposes only, and not for diagnostic or medical use. However, this clause is embedded deep into the Web site and surrounded by text like “disease risk prediction,” “predicted response to drugs,” and a long list of serious medical conditions that appear to be anything but entertainment- based. Together with mundane traits, such as bitter taste perception, freckling, earwax type, and hair thickness, consumers are tested for susceptibility to amyotrophic lateral sclerosis, bipolar disease, heroin addiction, and cancer predisposition. This strange combination of offerings makes it difficult to determine whether this testing is truly entertainmentbased or a serious predictive testing panel requiring careful interpretation by a medical professional.

Complicating these issues even further, several DTC testing companies do not fully explain which SNPs or gene mutations are evaluated in their specific disease risk profiles. Therefore, the average woman may think she has had comprehensive sequencing for BRCA1 and BRCA2 because her “breast cancer risk” has been assessed, when in fact she has been tested for a panel of low-risk SNPs and only the three common Jewish BRCA mutations. For a non-Jewish patient, these results would be virtually meaningless in terms of assessing hereditary risk.

Even well-versed genetics professionals may not be able to decipher the implications of tests offered by some companies. Recently, a cancer genetics professional reported that she reviewed a multigene-disease panel offered by one DTC genetic testing company that reportedly included testing for MYH-associated polyposis. When she discussed this test with the company, she discovered that it provided analysis for only one of the two common MYH mutations in Caucasians (unpublished, personal communication). These important omissions could lead both patients and clinicians to think that comprehensive testing has been performed when, in fact, it has not.

Counterpoint: DTC advertising has increased physician and patient awareness of genetic testing and technology.

As consumers become more sophisticated in their medical knowledge base, many are turning to the Internet for healthcare information before, or instead of, addressing their concerns with a medical professional. Although medical information on the Internet is of varied accuracy, obtaining medical information online is a trend that is here to stay, and genetic testing is no exception. The DTC genetic testing companies have exploited this thirst for medical information and have developed educational information on basic “Genetics 101” concepts for the lay public. For example, 23andMe, a DTC genetic testing company, describes genomic testing through an animated video clip using cartoon characters on its Web site. This new educational delivery system not only helps the genetic testing company sell their product but also helps the consumer learn more about genomic technology. In response to DTC genetic testing, many medical groups have launched educational campaigns to help bring clinicians up-to-date on the genetic testing their patients may be pursuing and bringing to their office.

Many professional medical organizations have addressed this gap in knowledge and have continually offered additional training regarding regarding the implications of genomic and genetic technologies in their subspeciality. Oncology has been at the forefront of this movement, offering training to oncologists through the American Society of Clinical Oncology to expand the knowledge base on genetic and genomic testing.

Is DTC genetic testing without the guidance of a qualified professional doing more harm than good?

Point: For consumers to have DTC testing without the guidance of a qualified professional to interpret complex information is not in their best interest.

Many DTC genetic testing companies allow consumers to order their own tests and provide results, risk calculations, and interpretations to patients without any contact with a knowledgeable clinician. As illustrated in the BRCA vignette below, the information provided to patients with their results is often not only inaccurate and irresponsible but may be harmful or deadly to the patient and at-risk family members.

An undercover investigation of DTC testing companies revealed poor to nonexistent medical advice from supposed consult experts, in addition to possible privacy concerns.14 Although some DTC genetic testing companies offer genetic counseling as part of their services, the consumer needs to be aware that medical advice from an individual with a financial interest in the product or company may be biased.21,22 Much as patients would not contact a pharmaceutical company to ask whether they should take a drug it supplies, patients should be wary of receiving advice regarding genetic testing from a company that stands to profit directly from their decision.

The complex information provided by these DTC genetic tests for disease risk is at best difficult to interpret, and there is concern that patients and physicians may make important healthcare decisions based on this information without a clear understanding of the test limitations. 18,23 A 2008 survey of physicians found that among those aware of personal genomic testing, 15% had a patient who had brought in test results for discussion, and more than 50% indicated that such tests would influence their decisions regarding patient care.24 Similarly, McGuire et al found that a majority (78%) of consumers report that they would take results of DTC genetic testing to their healthcare providers.25 These findings lend credence to the concerns expressed by several authors that DTC genetic testing may lead to overuse of the healthcare system, including unnecessary clinician visits and follow-up evaluations or tests.18,22,25–28

Many professional societies have issued DTC testing opinion statements that address the concern for misinterpretation of genetic test results without an appropriately trained professional and the need for federal regulation to protect consumers.18,29–31 Very recently, the American Medical Association issued a letter to the US Food and Drug Administration urging the agency to recommend that genetic testing be carried out under the supervision of a qualified healthcare professional.32

Counterpoint: DTC is a new service delivery model and provides information to consumers who may otherwise not have genetic testing.

Some DTC testing companies have employed genetic counselors on staff to be proactive in addressing patients’ concerns and questions about their results. And, although bias is a concern, certified genetic counselors working for these companies can provide basic information to consumers and will hopefully refer them to outside professionals to verify test results in a CLIA (Clinical Laboratory Improvement Amendments)-approved laboratory, provide personalized result interpretations based on the patients’ personal and family histories, and provide long-term patient and family follow-up. Some patients who undergo DTC testing may not have sought clinic-based genetic counseling and testing. Thus, this new model of genetic testing may allow more consumers and their families to access and benefit from genetic information.

Conclusion

DTC genetic testing is now widely available, with companies offering testing for a broad variety of traits and diseases, including several cancers. The disease risk information provided is typically based on SNP panels without demonstrated clinical validity or utility and may also include testing for a limited number of high-risk gene mutations. It can be difficult for even a knowledgeable genetics expert to separate out these data based on the limited information provided by these companies.

Although proponents of DTC genetic testing cite increased access, privacy, patient autonomy, and improved genetics knowledge, there is increasing concern among the scientific, medical, ethical, and legal communities that such testing is misleading and potentially harmful to patients as well as society and thus should be subject to increased regulation.5,15,18,22,28,30,33 As such regulation will take time, patients who inquire about DTC genetic testing for cancer risk should be cautioned that the information they receive may be inaccurate and misleading. Insofar as this new model of genetic testing has the potential to reach many consumers who would not otherwise have accessed testing, potential benefit and minimization of harm can be facilitated by involvement of a qualified genetics professional to allow for appropriate test interpretation in the context of medical and family histories.

References

1. Myers MF, Chang M-H, Jorgensen C, et al. Genetic testing for susceptibility to breast and ovarian cancer: evaluating the impact of a direct-to-consumer marketing campaign on physicians’ knowledge and practices. Genet Med 2006;8:361–370.
2. Janssens CJW, Gwinn M, Bradley LA, et al. A critical appraisal of the scientific basis of commercial genomic profiles used to assess health risks and personalized health interventions. Am J Hum Genet 2008;82:593–599.
3. Magnus D, Cho M, Cook-Deegan B. Direct-to-consumer genetic tests: beyond medical regulation? Genome Med 2009;1:17.
4. Eng C, Sharp R. Bioethical and clinical dilemmas of direct-to-consumer personal genomic testing: the problem of misattributed equivalence. Sci Transl Med 2010;2(17):17cm5.
5. Khoury MJ, McBride CM, Schully SD, et al. Centers for Disease Control and Prevention. The scientific foundation for personal genomics: recommendations from a National Institutes of Health-Centers for Disease Control and Prevention multidisciplinary workshop. Genet Med 2009;11:559–567.
6. Wacholder S, Haretge P, Prentice R. Performance of common genetic variants in breast cancer risk models. N Engl J Med 2010;363:986–993.
7. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007;25:1329–1333.
8. Mealiffe M, Stokowski R, Thees B, Prentice R, Pettinger M, Hinds D. Assessment of clinical validity of a breast cancer risk model combining genetic and clinical information. J Natl Cancer Inst 2010;102:1618–1627.
9. deCODE Genetics Web site. http://www. decode.com. Accessed March 13, 2011.
10. 23andME Web site. http://www.23andMe. com. Accessed March 13, 2011.
11. Navigenics Web site. http://www.navigenics. com. Accessed March 13, 2011.
12. Proactive Genomics Web site. http:// www.proactivegenomics.com. Accessed March 13, 2011.
13. Ng PC, Murray SS, Levy S, Venter JC. An agenda for personalized medicine. Nature 2009;461:724–726.
14. GAO report: Direct-to-consumer genetic tests: misleading test results are further complicated by deceptive marketing and other questionable practices. GAO-10-847T July 22, 2010. http://www.gao.gov/products/GAO-10- 847T. Accessed March 13, 2011.
15. Udesky L. The ethics of direct-to-consumer genetic testing. Lancet 2010;376:1377– 1378.
16. Berndt S, Platz E, Fallin M. Mismatch repair polymorphism and the risk of colorectal cancer. Int J Cancer 2007;120:1548–1554.
17. da Silva TD, Felipe AV, de Lima JM, Oshima CT, Forones NM. N-Acetyltransferase 2 genetic polymorphisms and risk of colorectal cancer. World J Gastroenterol 2011;17:760– 765.
18. Hogarth S, Javitt G, Melzer D. The current landscape for direct-to-consumer genetic testing: legal, ethical, and policy issues. Annu Rev Genomics Hum Genet 2008;9:161–182.
19. Gray S, Olopade OI. Direct-to-consumer marketing of genetics tests for cancer: buyer beware. J Clin Oncol 2003;21:3191– 3193.
20. Gollust SE, Chandros Hull S, Wilfond BS. Limitations of direct-to-consumer advertising for clinical genetic testing. JAMA 2002;288:1762–1767.
21. Wolfberg AJ. Genes on the Web: directto- consumer marketing of genetic testing. N Engl J Med 2006;355:543–545.
22. European Society of Human Genetics. Statement of the ESHG on direct-to-consumer genetic testing for health-related purposes. Eur J Hum Genet 2010;18:1271–1273.
23. Williams-Jones B. “Be ready against cancer, now”: direct-to-consumer advertising for genetic testing. New Genet Soc 2006;25:89–107.
24. Kolar K, Liu T, St Pierre J, Khoury MJ. Heath care provider and consumer awareness, perceptions, and use of direct-to-consumer personal genomic tests. Genet Med 2009;11:595.
25. McGuire AL, Diaz C, Wang T, et al. Social networkers’ attitudes toward direct-toconsumer personal genome testing. Am J Bioethics 2009;9:3–10.
26. McGuire AL, Burke W. An unwelcome side effect of direct-to consumer personal genome testing: raiding the medical commons. JAMA 2008;300:2669–2671.
27. Caufield T, Ries NM, Ray PN, Shuman C, Wilson B. Direct-to-consumer genetic testing: good, bad or benign? Clin Genetic 2010;77:101–105.
28. Mykitiuk R. Caveat emptor: direct-toconsumer supply and advertising of genetic testing. Clin Invest Med 2004;27:23–32.
29. American College of Medical Genetics (ACMG) statement on direct-to-consumer genetic testing: April 7, 2008. http://www. acmg.net/AM/Template.cfm?Section=Policy_ Statements&Template=/CM/ContentDisplay. cfm&ContentID=2975, Accessed March 13, 2011.
30. Hudson K, Javitt G, Burke W. ASHG statement on direct-to-consumer genetic testing in the United States. Obstet Gynecol 2007;110:1392–1395.
31. NSGC statement on direct to consumer genetic testing. Adopted 2007. http://www. nsgc.org/Media/PositionStatements/tabid/ 330/Default.aspx#DTC. Accessed March 13, 2011.
32. AMA Press Release, February 23, 2011. AMA to FDA: genetic testing should be conducted by qualified health professionals. http:// www.ama-assn.org/ama/pub/news/news/genetic- testing-qualified-professionals.page. Accessed March 8, 2011.
33. Annes JP, Giovanni MA, Murray MF. Risk of presymptomatic direct-to-consumer genetic testing. N Engl J Med 2010;363:1100–1101.

The genomic revolution has the potential to change the practice of medicine and healthcare. Advances in technology are driving down the cost of genetic testing, the public is more aware of and interested in such testing and its uses, and genetic testing companies are now offering direct-to-consumer (DTC) testing via kits sold on the Internet. Some argue that these changes make genetic testing more accessible to the general public and medical community at large and that these changes are critical to the full integration of genomic technology into society. However, many of the DTC tests offered are of questionable accuracy and utility and combine tests that provide mundane information about genetic traits with those for serious genetic conditions with life-threatening implications for the patient and the entire family. We will examine both sides of the issues surrounding DTC genetic testing, focusing on important considerations for clinicians using case vignettes to illustrate key issues.

Is DTC testing worthwhile for your patients?

Point: The testing and result interpretations provided are not necessarily clinically accurate or helpful.

Numerous studies have shown that average patients and clinicians are not well versed on even the most basic elements of genetic testing and result interpretation. 1 It is even less likely that consumers and clinicians will understand the subtle differences between DTC companies and tests—particularly genomic profiling based on single nucleotide polymorphisms (SNPs)—which are offered by most DTC companies. The difference between SNPbased testing and clinical single-gene testing with regard to predictive value is a confusing concept that typical consumers and clinicians without adequate training may not understand. For most of the SNP-based genomic profiles offered DTC, there is a lack of consensus among the scientific and medical communities regarding test interpretation.

The positive and negative predictive values, along with the discriminatory accuracy of these tests, are in sharp contrast to those associated with testing for mutations in high-penetrance Mendelian genes. Discriminatory accuracy refers to the ability of a test to determine who will or will not develop the disease or condition and is a balance between sensitivity and specificity. For example, those who test positive for a mutation in the Huntington's disease gene are certain to develop the disease, whereas those who test negative are unlikely to do so. Similarly, in cancer genetics, those with a mutation in the APC gene (causative of familial adenomatous polyposis) will develop colon polyps and colon cancer without appropriate intervention.

With these Mendelian conditions, the relative risk of disease (penetrance) is large (often 10-fold or greater), and the proportion of disease attribestimated by these companies fail to account for known family history or other risk factors. An investigation in July 2010 by the US General Accounting Office concluded that such tests were “misleading and of little or no practical use.”14 The risk profiles provided by such companies have been described as having “no predictive value” and may falsely alarm or reassure consumers.15

Counterpoint: Individuals have the right to explore their own genetic makeup through these emerging tests and may deem testing worthwhile. Some individuals may learn important information they would otherwise not have learned.

One argument to be made is that genetic technology exists and individuals have the right to explore the testing available, regardless of its accuracy and utility. Many DTC sites do state that their testing is intended for entertainment purposes only, although this statement is often in the fine print (see next point). It is possible that DTC testing has made the public more aware of genetic and genomic testing, therefore encouraging the medical profession to keep up with this technology as it pertains to one's area of expertise. Although some may see this as an additional burden on the primary care provider, it can also be viewed as an opportunity to increase awareness and education on the part of both the consumer and the professional. Most current genomic technology was not developed when most of today’s physicians went to medical school, and even most new graduates are not well versed in genetic testing. DTC genetic testing could encourage the medical community to increase its understanding of this new emerging technology.

Although most of the DTC testing offered is of questionable utility, some panels do include important genetic information, like the three common Jewish BRCA mutations. It may be considered ethically questionable to offer testing for hereditary breast cancer and ovarian cancer without full informed consent and adequate result disclosure. However, one can also argue that individuals will gain potentially lifesaving information they might never have uncovered without such testing.

Proponents of DTC genomic profiling suggest that the clinical usefulness of SNP-based testing will improve based on emerging data that analyze the interaction between genetic polymorphisms and environmental factors in predicting disease risk. For example, preliminary studies evaluating SNPs associated with colorectal cancer have found that relative risks are increased when combined with environmental factors, such as high intake of processed meats.16,17 Despite these early findings, it remains to be seen whether the complexity of gene-environment and gene-gene interactions can be elucidated to the extent that will be required to yield highly predictive DTC tests.

Is DTC advertising accurate, fair, and helpful?

Point: DTC advertising overemphasizes the benefits of testing and does not adequately describe the limitations and risks.

Unlike pharmaceutical advertising, which is tightly regulated and requires companies to discuss associated risks, oversight of genetic testing advertisements is limited.18 This can lead to skewing of information that overemphasizes the benefits of genetic testing and does not adequately define the risks and limitations.19,20 One recent study demonstrated that when individuals are provided with accurate information regarding the actual risks and limitations of online DTC genetic testing, they have reduced intentions to obtain such tests and less positive views of Internet-based testing. 19 Furthermore, an investigation of DTC advertising revealed “egregious examples” of deceptive marketing, such as claims that consumers’ DNA could be used to create personalized supplements to cure disease or that results of such DNA tests could be used to predict the athletic potential of their children.14

Many DTC companies have a clause indicating that their testing is intended for research, educational, or entertainment purposes only, and not for diagnostic or medical use. However, this clause is embedded deep into the Web site and surrounded by text like “disease risk prediction,” “predicted response to drugs,” and a long list of serious medical conditions that appear to be anything but entertainment- based. Together with mundane traits, such as bitter taste perception, freckling, earwax type, and hair thickness, consumers are tested for susceptibility to amyotrophic lateral sclerosis, bipolar disease, heroin addiction, and cancer predisposition. This strange combination of offerings makes it difficult to determine whether this testing is truly entertainmentbased or a serious predictive testing panel requiring careful interpretation by a medical professional.

Complicating these issues even further, several DTC testing companies do not fully explain which SNPs or gene mutations are evaluated in their specific disease risk profiles. Therefore, the average woman may think she has had comprehensive sequencing for BRCA1 and BRCA2 because her “breast cancer risk” has been assessed, when in fact she has been tested for a panel of low-risk SNPs and only the three common Jewish BRCA mutations. For a non-Jewish patient, these results would be virtually meaningless in terms of assessing hereditary risk.

Even well-versed genetics professionals may not be able to decipher the implications of tests offered by some companies. Recently, a cancer genetics professional reported that she reviewed a multigene-disease panel offered by one DTC genetic testing company that reportedly included testing for MYH-associated polyposis. When she discussed this test with the company, she discovered that it provided analysis for only one of the two common MYH mutations in Caucasians (unpublished, personal communication). These important omissions could lead both patients and clinicians to think that comprehensive testing has been performed when, in fact, it has not.

Counterpoint: DTC advertising has increased physician and patient awareness of genetic testing and technology.

As consumers become more sophisticated in their medical knowledge base, many are turning to the Internet for healthcare information before, or instead of, addressing their concerns with a medical professional. Although medical information on the Internet is of varied accuracy, obtaining medical information online is a trend that is here to stay, and genetic testing is no exception. The DTC genetic testing companies have exploited this thirst for medical information and have developed educational information on basic “Genetics 101” concepts for the lay public. For example, 23andMe, a DTC genetic testing company, describes genomic testing through an animated video clip using cartoon characters on its Web site. This new educational delivery system not only helps the genetic testing company sell their product but also helps the consumer learn more about genomic technology. In response to DTC genetic testing, many medical groups have launched educational campaigns to help bring clinicians up-to-date on the genetic testing their patients may be pursuing and bringing to their office.

Many professional medical organizations have addressed this gap in knowledge and have continually offered additional training regarding regarding the implications of genomic and genetic technologies in their subspeciality. Oncology has been at the forefront of this movement, offering training to oncologists through the American Society of Clinical Oncology to expand the knowledge base on genetic and genomic testing.

Is DTC genetic testing without the guidance of a qualified professional doing more harm than good?

Point: For consumers to have DTC testing without the guidance of a qualified professional to interpret complex information is not in their best interest.

Many DTC genetic testing companies allow consumers to order their own tests and provide results, risk calculations, and interpretations to patients without any contact with a knowledgeable clinician. As illustrated in the BRCA vignette below, the information provided to patients with their results is often not only inaccurate and irresponsible but may be harmful or deadly to the patient and at-risk family members.

An undercover investigation of DTC testing companies revealed poor to nonexistent medical advice from supposed consult experts, in addition to possible privacy concerns.14 Although some DTC genetic testing companies offer genetic counseling as part of their services, the consumer needs to be aware that medical advice from an individual with a financial interest in the product or company may be biased.21,22 Much as patients would not contact a pharmaceutical company to ask whether they should take a drug it supplies, patients should be wary of receiving advice regarding genetic testing from a company that stands to profit directly from their decision.

The complex information provided by these DTC genetic tests for disease risk is at best difficult to interpret, and there is concern that patients and physicians may make important healthcare decisions based on this information without a clear understanding of the test limitations. 18,23 A 2008 survey of physicians found that among those aware of personal genomic testing, 15% had a patient who had brought in test results for discussion, and more than 50% indicated that such tests would influence their decisions regarding patient care.24 Similarly, McGuire et al found that a majority (78%) of consumers report that they would take results of DTC genetic testing to their healthcare providers.25 These findings lend credence to the concerns expressed by several authors that DTC genetic testing may lead to overuse of the healthcare system, including unnecessary clinician visits and follow-up evaluations or tests.18,22,25–28

Many professional societies have issued DTC testing opinion statements that address the concern for misinterpretation of genetic test results without an appropriately trained professional and the need for federal regulation to protect consumers.18,29–31 Very recently, the American Medical Association issued a letter to the US Food and Drug Administration urging the agency to recommend that genetic testing be carried out under the supervision of a qualified healthcare professional.32

Counterpoint: DTC is a new service delivery model and provides information to consumers who may otherwise not have genetic testing.

Some DTC testing companies have employed genetic counselors on staff to be proactive in addressing patients’ concerns and questions about their results. And, although bias is a concern, certified genetic counselors working for these companies can provide basic information to consumers and will hopefully refer them to outside professionals to verify test results in a CLIA (Clinical Laboratory Improvement Amendments)-approved laboratory, provide personalized result interpretations based on the patients’ personal and family histories, and provide long-term patient and family follow-up. Some patients who undergo DTC testing may not have sought clinic-based genetic counseling and testing. Thus, this new model of genetic testing may allow more consumers and their families to access and benefit from genetic information.

Conclusion

DTC genetic testing is now widely available, with companies offering testing for a broad variety of traits and diseases, including several cancers. The disease risk information provided is typically based on SNP panels without demonstrated clinical validity or utility and may also include testing for a limited number of high-risk gene mutations. It can be difficult for even a knowledgeable genetics expert to separate out these data based on the limited information provided by these companies.

Although proponents of DTC genetic testing cite increased access, privacy, patient autonomy, and improved genetics knowledge, there is increasing concern among the scientific, medical, ethical, and legal communities that such testing is misleading and potentially harmful to patients as well as society and thus should be subject to increased regulation.5,15,18,22,28,30,33 As such regulation will take time, patients who inquire about DTC genetic testing for cancer risk should be cautioned that the information they receive may be inaccurate and misleading. Insofar as this new model of genetic testing has the potential to reach many consumers who would not otherwise have accessed testing, potential benefit and minimization of harm can be facilitated by involvement of a qualified genetics professional to allow for appropriate test interpretation in the context of medical and family histories.

References

1. Myers MF, Chang M-H, Jorgensen C, et al. Genetic testing for susceptibility to breast and ovarian cancer: evaluating the impact of a direct-to-consumer marketing campaign on physicians’ knowledge and practices. Genet Med 2006;8:361–370.
2. Janssens CJW, Gwinn M, Bradley LA, et al. A critical appraisal of the scientific basis of commercial genomic profiles used to assess health risks and personalized health interventions. Am J Hum Genet 2008;82:593–599.
3. Magnus D, Cho M, Cook-Deegan B. Direct-to-consumer genetic tests: beyond medical regulation? Genome Med 2009;1:17.
4. Eng C, Sharp R. Bioethical and clinical dilemmas of direct-to-consumer personal genomic testing: the problem of misattributed equivalence. Sci Transl Med 2010;2(17):17cm5.
5. Khoury MJ, McBride CM, Schully SD, et al. Centers for Disease Control and Prevention. The scientific foundation for personal genomics: recommendations from a National Institutes of Health-Centers for Disease Control and Prevention multidisciplinary workshop. Genet Med 2009;11:559–567.
6. Wacholder S, Haretge P, Prentice R. Performance of common genetic variants in breast cancer risk models. N Engl J Med 2010;363:986–993.
7. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007;25:1329–1333.
8. Mealiffe M, Stokowski R, Thees B, Prentice R, Pettinger M, Hinds D. Assessment of clinical validity of a breast cancer risk model combining genetic and clinical information. J Natl Cancer Inst 2010;102:1618–1627.
9. deCODE Genetics Web site. http://www. decode.com. Accessed March 13, 2011.
10. 23andME Web site. http://www.23andMe. com. Accessed March 13, 2011.
11. Navigenics Web site. http://www.navigenics. com. Accessed March 13, 2011.
12. Proactive Genomics Web site. http:// www.proactivegenomics.com. Accessed March 13, 2011.
13. Ng PC, Murray SS, Levy S, Venter JC. An agenda for personalized medicine. Nature 2009;461:724–726.
14. GAO report: Direct-to-consumer genetic tests: misleading test results are further complicated by deceptive marketing and other questionable practices. GAO-10-847T July 22, 2010. http://www.gao.gov/products/GAO-10- 847T. Accessed March 13, 2011.
15. Udesky L. The ethics of direct-to-consumer genetic testing. Lancet 2010;376:1377– 1378.
16. Berndt S, Platz E, Fallin M. Mismatch repair polymorphism and the risk of colorectal cancer. Int J Cancer 2007;120:1548–1554.
17. da Silva TD, Felipe AV, de Lima JM, Oshima CT, Forones NM. N-Acetyltransferase 2 genetic polymorphisms and risk of colorectal cancer. World J Gastroenterol 2011;17:760– 765.
18. Hogarth S, Javitt G, Melzer D. The current landscape for direct-to-consumer genetic testing: legal, ethical, and policy issues. Annu Rev Genomics Hum Genet 2008;9:161–182.
19. Gray S, Olopade OI. Direct-to-consumer marketing of genetics tests for cancer: buyer beware. J Clin Oncol 2003;21:3191– 3193.
20. Gollust SE, Chandros Hull S, Wilfond BS. Limitations of direct-to-consumer advertising for clinical genetic testing. JAMA 2002;288:1762–1767.
21. Wolfberg AJ. Genes on the Web: directto- consumer marketing of genetic testing. N Engl J Med 2006;355:543–545.
22. European Society of Human Genetics. Statement of the ESHG on direct-to-consumer genetic testing for health-related purposes. Eur J Hum Genet 2010;18:1271–1273.
23. Williams-Jones B. “Be ready against cancer, now”: direct-to-consumer advertising for genetic testing. New Genet Soc 2006;25:89–107.
24. Kolar K, Liu T, St Pierre J, Khoury MJ. Heath care provider and consumer awareness, perceptions, and use of direct-to-consumer personal genomic tests. Genet Med 2009;11:595.
25. McGuire AL, Diaz C, Wang T, et al. Social networkers’ attitudes toward direct-toconsumer personal genome testing. Am J Bioethics 2009;9:3–10.
26. McGuire AL, Burke W. An unwelcome side effect of direct-to consumer personal genome testing: raiding the medical commons. JAMA 2008;300:2669–2671.
27. Caufield T, Ries NM, Ray PN, Shuman C, Wilson B. Direct-to-consumer genetic testing: good, bad or benign? Clin Genetic 2010;77:101–105.
28. Mykitiuk R. Caveat emptor: direct-toconsumer supply and advertising of genetic testing. Clin Invest Med 2004;27:23–32.
29. American College of Medical Genetics (ACMG) statement on direct-to-consumer genetic testing: April 7, 2008. http://www. acmg.net/AM/Template.cfm?Section=Policy_ Statements&Template=/CM/ContentDisplay. cfm&ContentID=2975, Accessed March 13, 2011.
30. Hudson K, Javitt G, Burke W. ASHG statement on direct-to-consumer genetic testing in the United States. Obstet Gynecol 2007;110:1392–1395.
31. NSGC statement on direct to consumer genetic testing. Adopted 2007. http://www. nsgc.org/Media/PositionStatements/tabid/ 330/Default.aspx#DTC. Accessed March 13, 2011.
32. AMA Press Release, February 23, 2011. AMA to FDA: genetic testing should be conducted by qualified health professionals. http:// www.ama-assn.org/ama/pub/news/news/genetic- testing-qualified-professionals.page. Accessed March 8, 2011.
33. Annes JP, Giovanni MA, Murray MF. Risk of presymptomatic direct-to-consumer genetic testing. N Engl J Med 2010;363:1100–1101.

The genomic revolution has the potential to change the practice of medicine and healthcare. Advances in technology are driving down the cost of genetic testing, the public is more aware of and interested in such testing and its uses, and genetic testing companies are now offering direct-to-consumer (DTC) testing via kits sold on the Internet. Some argue that these changes make genetic testing more accessible to the general public and medical community at large and that these changes are critical to the full integration of genomic technology into society. However, many of the DTC tests offered are of questionable accuracy and utility and combine tests that provide mundane information about genetic traits with those for serious genetic conditions with life-threatening implications for the patient and the entire family. We will examine both sides of the issues surrounding DTC genetic testing, focusing on important considerations for clinicians using case vignettes to illustrate key issues.

Is DTC testing worthwhile for your patients?

Point: The testing and result interpretations provided are not necessarily clinically accurate or helpful.

Numerous studies have shown that average patients and clinicians are not well versed on even the most basic elements of genetic testing and result interpretation. 1 It is even less likely that consumers and clinicians will understand the subtle differences between DTC companies and tests—particularly genomic profiling based on single nucleotide polymorphisms (SNPs)—which are offered by most DTC companies. The difference between SNPbased testing and clinical single-gene testing with regard to predictive value is a confusing concept that typical consumers and clinicians without adequate training may not understand. For most of the SNP-based genomic profiles offered DTC, there is a lack of consensus among the scientific and medical communities regarding test interpretation.

The positive and negative predictive values, along with the discriminatory accuracy of these tests, are in sharp contrast to those associated with testing for mutations in high-penetrance Mendelian genes. Discriminatory accuracy refers to the ability of a test to determine who will or will not develop the disease or condition and is a balance between sensitivity and specificity. For example, those who test positive for a mutation in the Huntington's disease gene are certain to develop the disease, whereas those who test negative are unlikely to do so. Similarly, in cancer genetics, those with a mutation in the APC gene (causative of familial adenomatous polyposis) will develop colon polyps and colon cancer without appropriate intervention.

With these Mendelian conditions, the relative risk of disease (penetrance) is large (often 10-fold or greater), and the proportion of disease attribestimated by these companies fail to account for known family history or other risk factors. An investigation in July 2010 by the US General Accounting Office concluded that such tests were “misleading and of little or no practical use.”14 The risk profiles provided by such companies have been described as having “no predictive value” and may falsely alarm or reassure consumers.15

Counterpoint: Individuals have the right to explore their own genetic makeup through these emerging tests and may deem testing worthwhile. Some individuals may learn important information they would otherwise not have learned.

One argument to be made is that genetic technology exists and individuals have the right to explore the testing available, regardless of its accuracy and utility. Many DTC sites do state that their testing is intended for entertainment purposes only, although this statement is often in the fine print (see next point). It is possible that DTC testing has made the public more aware of genetic and genomic testing, therefore encouraging the medical profession to keep up with this technology as it pertains to one's area of expertise. Although some may see this as an additional burden on the primary care provider, it can also be viewed as an opportunity to increase awareness and education on the part of both the consumer and the professional. Most current genomic technology was not developed when most of today’s physicians went to medical school, and even most new graduates are not well versed in genetic testing. DTC genetic testing could encourage the medical community to increase its understanding of this new emerging technology.

Although most of the DTC testing offered is of questionable utility, some panels do include important genetic information, like the three common Jewish BRCA mutations. It may be considered ethically questionable to offer testing for hereditary breast cancer and ovarian cancer without full informed consent and adequate result disclosure. However, one can also argue that individuals will gain potentially lifesaving information they might never have uncovered without such testing.

Proponents of DTC genomic profiling suggest that the clinical usefulness of SNP-based testing will improve based on emerging data that analyze the interaction between genetic polymorphisms and environmental factors in predicting disease risk. For example, preliminary studies evaluating SNPs associated with colorectal cancer have found that relative risks are increased when combined with environmental factors, such as high intake of processed meats.16,17 Despite these early findings, it remains to be seen whether the complexity of gene-environment and gene-gene interactions can be elucidated to the extent that will be required to yield highly predictive DTC tests.

Is DTC advertising accurate, fair, and helpful?

Point: DTC advertising overemphasizes the benefits of testing and does not adequately describe the limitations and risks.

Unlike pharmaceutical advertising, which is tightly regulated and requires companies to discuss associated risks, oversight of genetic testing advertisements is limited.18 This can lead to skewing of information that overemphasizes the benefits of genetic testing and does not adequately define the risks and limitations.19,20 One recent study demonstrated that when individuals are provided with accurate information regarding the actual risks and limitations of online DTC genetic testing, they have reduced intentions to obtain such tests and less positive views of Internet-based testing. 19 Furthermore, an investigation of DTC advertising revealed “egregious examples” of deceptive marketing, such as claims that consumers’ DNA could be used to create personalized supplements to cure disease or that results of such DNA tests could be used to predict the athletic potential of their children.14

Many DTC companies have a clause indicating that their testing is intended for research, educational, or entertainment purposes only, and not for diagnostic or medical use. However, this clause is embedded deep into the Web site and surrounded by text like “disease risk prediction,” “predicted response to drugs,” and a long list of serious medical conditions that appear to be anything but entertainment- based. Together with mundane traits, such as bitter taste perception, freckling, earwax type, and hair thickness, consumers are tested for susceptibility to amyotrophic lateral sclerosis, bipolar disease, heroin addiction, and cancer predisposition. This strange combination of offerings makes it difficult to determine whether this testing is truly entertainmentbased or a serious predictive testing panel requiring careful interpretation by a medical professional.

Complicating these issues even further, several DTC testing companies do not fully explain which SNPs or gene mutations are evaluated in their specific disease risk profiles. Therefore, the average woman may think she has had comprehensive sequencing for BRCA1 and BRCA2 because her “breast cancer risk” has been assessed, when in fact she has been tested for a panel of low-risk SNPs and only the three common Jewish BRCA mutations. For a non-Jewish patient, these results would be virtually meaningless in terms of assessing hereditary risk.

Even well-versed genetics professionals may not be able to decipher the implications of tests offered by some companies. Recently, a cancer genetics professional reported that she reviewed a multigene-disease panel offered by one DTC genetic testing company that reportedly included testing for MYH-associated polyposis. When she discussed this test with the company, she discovered that it provided analysis for only one of the two common MYH mutations in Caucasians (unpublished, personal communication). These important omissions could lead both patients and clinicians to think that comprehensive testing has been performed when, in fact, it has not.

Counterpoint: DTC advertising has increased physician and patient awareness of genetic testing and technology.

As consumers become more sophisticated in their medical knowledge base, many are turning to the Internet for healthcare information before, or instead of, addressing their concerns with a medical professional. Although medical information on the Internet is of varied accuracy, obtaining medical information online is a trend that is here to stay, and genetic testing is no exception. The DTC genetic testing companies have exploited this thirst for medical information and have developed educational information on basic “Genetics 101” concepts for the lay public. For example, 23andMe, a DTC genetic testing company, describes genomic testing through an animated video clip using cartoon characters on its Web site. This new educational delivery system not only helps the genetic testing company sell their product but also helps the consumer learn more about genomic technology. In response to DTC genetic testing, many medical groups have launched educational campaigns to help bring clinicians up-to-date on the genetic testing their patients may be pursuing and bringing to their office.

Many professional medical organizations have addressed this gap in knowledge and have continually offered additional training regarding regarding the implications of genomic and genetic technologies in their subspeciality. Oncology has been at the forefront of this movement, offering training to oncologists through the American Society of Clinical Oncology to expand the knowledge base on genetic and genomic testing.

Is DTC genetic testing without the guidance of a qualified professional doing more harm than good?

Point: For consumers to have DTC testing without the guidance of a qualified professional to interpret complex information is not in their best interest.

Many DTC genetic testing companies allow consumers to order their own tests and provide results, risk calculations, and interpretations to patients without any contact with a knowledgeable clinician. As illustrated in the BRCA vignette below, the information provided to patients with their results is often not only inaccurate and irresponsible but may be harmful or deadly to the patient and at-risk family members.

An undercover investigation of DTC testing companies revealed poor to nonexistent medical advice from supposed consult experts, in addition to possible privacy concerns.14 Although some DTC genetic testing companies offer genetic counseling as part of their services, the consumer needs to be aware that medical advice from an individual with a financial interest in the product or company may be biased.21,22 Much as patients would not contact a pharmaceutical company to ask whether they should take a drug it supplies, patients should be wary of receiving advice regarding genetic testing from a company that stands to profit directly from their decision.

The complex information provided by these DTC genetic tests for disease risk is at best difficult to interpret, and there is concern that patients and physicians may make important healthcare decisions based on this information without a clear understanding of the test limitations. 18,23 A 2008 survey of physicians found that among those aware of personal genomic testing, 15% had a patient who had brought in test results for discussion, and more than 50% indicated that such tests would influence their decisions regarding patient care.24 Similarly, McGuire et al found that a majority (78%) of consumers report that they would take results of DTC genetic testing to their healthcare providers.25 These findings lend credence to the concerns expressed by several authors that DTC genetic testing may lead to overuse of the healthcare system, including unnecessary clinician visits and follow-up evaluations or tests.18,22,25–28

Many professional societies have issued DTC testing opinion statements that address the concern for misinterpretation of genetic test results without an appropriately trained professional and the need for federal regulation to protect consumers.18,29–31 Very recently, the American Medical Association issued a letter to the US Food and Drug Administration urging the agency to recommend that genetic testing be carried out under the supervision of a qualified healthcare professional.32

Counterpoint: DTC is a new service delivery model and provides information to consumers who may otherwise not have genetic testing.

Some DTC testing companies have employed genetic counselors on staff to be proactive in addressing patients’ concerns and questions about their results. And, although bias is a concern, certified genetic counselors working for these companies can provide basic information to consumers and will hopefully refer them to outside professionals to verify test results in a CLIA (Clinical Laboratory Improvement Amendments)-approved laboratory, provide personalized result interpretations based on the patients’ personal and family histories, and provide long-term patient and family follow-up. Some patients who undergo DTC testing may not have sought clinic-based genetic counseling and testing. Thus, this new model of genetic testing may allow more consumers and their families to access and benefit from genetic information.

Conclusion

DTC genetic testing is now widely available, with companies offering testing for a broad variety of traits and diseases, including several cancers. The disease risk information provided is typically based on SNP panels without demonstrated clinical validity or utility and may also include testing for a limited number of high-risk gene mutations. It can be difficult for even a knowledgeable genetics expert to separate out these data based on the limited information provided by these companies.

Although proponents of DTC genetic testing cite increased access, privacy, patient autonomy, and improved genetics knowledge, there is increasing concern among the scientific, medical, ethical, and legal communities that such testing is misleading and potentially harmful to patients as well as society and thus should be subject to increased regulation.5,15,18,22,28,30,33 As such regulation will take time, patients who inquire about DTC genetic testing for cancer risk should be cautioned that the information they receive may be inaccurate and misleading. Insofar as this new model of genetic testing has the potential to reach many consumers who would not otherwise have accessed testing, potential benefit and minimization of harm can be facilitated by involvement of a qualified genetics professional to allow for appropriate test interpretation in the context of medical and family histories.

References

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14. GAO report: Direct-to-consumer genetic tests: misleading test results are further complicated by deceptive marketing and other questionable practices. GAO-10-847T July 22, 2010. http://www.gao.gov/products/GAO-10- 847T. Accessed March 13, 2011.
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18. Hogarth S, Javitt G, Melzer D. The current landscape for direct-to-consumer genetic testing: legal, ethical, and policy issues. Annu Rev Genomics Hum Genet 2008;9:161–182.
19. Gray S, Olopade OI. Direct-to-consumer marketing of genetics tests for cancer: buyer beware. J Clin Oncol 2003;21:3191– 3193.
20. Gollust SE, Chandros Hull S, Wilfond BS. Limitations of direct-to-consumer advertising for clinical genetic testing. JAMA 2002;288:1762–1767.
21. Wolfberg AJ. Genes on the Web: directto- consumer marketing of genetic testing. N Engl J Med 2006;355:543–545.
22. European Society of Human Genetics. Statement of the ESHG on direct-to-consumer genetic testing for health-related purposes. Eur J Hum Genet 2010;18:1271–1273.
23. Williams-Jones B. “Be ready against cancer, now”: direct-to-consumer advertising for genetic testing. New Genet Soc 2006;25:89–107.
24. Kolar K, Liu T, St Pierre J, Khoury MJ. Heath care provider and consumer awareness, perceptions, and use of direct-to-consumer personal genomic tests. Genet Med 2009;11:595.
25. McGuire AL, Diaz C, Wang T, et al. Social networkers’ attitudes toward direct-toconsumer personal genome testing. Am J Bioethics 2009;9:3–10.
26. McGuire AL, Burke W. An unwelcome side effect of direct-to consumer personal genome testing: raiding the medical commons. JAMA 2008;300:2669–2671.
27. Caufield T, Ries NM, Ray PN, Shuman C, Wilson B. Direct-to-consumer genetic testing: good, bad or benign? Clin Genetic 2010;77:101–105.
28. Mykitiuk R. Caveat emptor: direct-toconsumer supply and advertising of genetic testing. Clin Invest Med 2004;27:23–32.
29. American College of Medical Genetics (ACMG) statement on direct-to-consumer genetic testing: April 7, 2008. http://www. acmg.net/AM/Template.cfm?Section=Policy_ Statements&Template=/CM/ContentDisplay. cfm&ContentID=2975, Accessed March 13, 2011.
30. Hudson K, Javitt G, Burke W. ASHG statement on direct-to-consumer genetic testing in the United States. Obstet Gynecol 2007;110:1392–1395.
31. NSGC statement on direct to consumer genetic testing. Adopted 2007. http://www. nsgc.org/Media/PositionStatements/tabid/ 330/Default.aspx#DTC. Accessed March 13, 2011.
32. AMA Press Release, February 23, 2011. AMA to FDA: genetic testing should be conducted by qualified health professionals. http:// www.ama-assn.org/ama/pub/news/news/genetic- testing-qualified-professionals.page. Accessed March 8, 2011.
33. Annes JP, Giovanni MA, Murray MF. Risk of presymptomatic direct-to-consumer genetic testing. N Engl J Med 2010;363:1100–1101.