ANRV353-GG09-09 ARI 30 July 2008 4:18

The Current Landscape forDirect-to-Consumer GeneticTesting: Legal, Ethical, andPolicy IssuesStuart Hogarth,1 Gail Javitt,2 and David Melzer3

1Department of Social Sciences, Loughborough University, Loughborough LE11 3TU,United Kingdom; email: s.hogarth@lboro.ac.uk2Genetics and Public Policy Center, Johns Hopkins University, Washington, DC 20036;email: gjavitt1@jhu.edu3Epidemiology and Public Health Group, Peninsula Medical School, Exeter EX2 5DW,United Kingdom; email: david.melzer@pms.ac.uk

Annu. Rev. Genomics Hum. Genet. 2008. 9:161–82

The Annual Review of Genomics and Human Geneticsis online at genom.annualreviews.org

This article’s doi:10.1146/annurev.genom.9.081307.164319

Copyright c© 2008 by Annual Reviews.All rights reserved

1527-8204/08/0922-0161$20.00

Key Words

personalized genomics, government regulation, DNA profiling

AbstractThis review surveys the developing market for direct-to-consumer(DTC) genetic tests and examines the range of companies and testsavailable, the regulatory landscape, the concerns raised about DTCtesting, and the calls for enhanced oversight. We provide a comparativeoverview of the situation, particularly in the United States and Europe,by exploring the regulatory frameworks for medical devices and clini-cal laboratories. We also discuss a variety of other mechanisms such asgeneral controls on advertising and consumer law mechanisms.

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DTC: direct toconsumer

INTRODUCTIONDirect-to-consumer (DTC) genetic testing is agrowing phenomenon in the United States and(to a lesser extent) internationally. Harnessingthe power of the Internet and the promise ofthe Human Genome Project, and fueled by thepotential for profit and consumer interest inself-mediated healthcare, an increasing num-ber of companies are starting to offer health-related genetic testing services directly to thepublic.

The advent of DTC genetic testing hassparked considerable alarm among geneticists,public health and consumer advocates, and gov-ernmental bodies (4, 36, 37, 46, 59, 77, 86, 90).Critics of DTC genetic testing have raised anumber of concerns: the quality of the tests, theaccuracy and adequacy of the information pro-vided by companies, and the risk that consumersmay be misled by false or misleading claims andmay make harmful healthcare decisions on thebasis of test results (36, 37, 48, 89). Some haveasserted that genetic testing should take placeonly through a healthcare provider and withadequate counseling (4). Conversely, advocatesof DTC testing—primarily representing pur-veyors of DTC tests—contend that a DTC ap-proach enables greater consumer awareness ofand access to tests. These tests can help themimprove their health and make beneficial treat-ment and lifestyle decisions (10). These groupsalso claim that DTC testing provides a pri-vacy advantage over testing through a health-care provider (90). Little empirical evidenceexists regarding the impact of DTC testing onthe public.

Government oversight of DTC genetictesting—as with genetic testing generally—isquite limited. Most genetic tests are not subjectto any type of government review before theyare made available to the public. Federal re-quirements for genetic testing laboratories aregeneral in nature and do not set specific stan-dards for genetic tests. Thus, DTC companiesface few barriers to market entry, and few gov-ernmental mechanisms exist to ensure that lab-oratories reliably obtain the correct result or

that the tests they perform accurately predictphenotype.

The dynamic nature of the DTC market-place makes it a somewhat difficult topic fora review article. Some DTC company websitesthat existed five years ago have disappeared, andthose that are around today may not surviveuntil this review’s publication date. Despite theinherent fluidity of the marketplace, the com-mercial allure of DTC testing, coupled with thelack of regulatory barriers to market entry, hasled to a steady stream of new entrants; currentlymore than two dozen DTC companies existworldwide. Although some individual playersmay change, the phenomenon can be expectedto grow in the absence of regulatory changes.Moreover, DTC offerings are expanding to in-clude not only single-gene tests but also large-scale single-nucleotide polymorphism (SNP)profiling. Eventually, whole-genome sequenc-ing may be offered affordably in a DTCfashion.

Given the expansive potential of DTC ge-netic testing, it is important to understandthe regulatory framework in which DTC ge-netic tests are offered and the regulatory ap-proaches that different countries have adopted.This review defines genetic testing, describesthe types of genetic tests that are available,and explains the purposes for which they maybe used. We then define DTC genetic test-ing, discuss the concerns that have been raisedabout specific tests (both tests currently offeredand those expected to be offered in the fu-ture) discuss concerns about DTC marketingin general, and describe what is known empiri-cally about consumer and provider awareness ofDTC tests. Next, we summarize the regulationof DTC genetic testing in the United Statesand internationally, with particular focus on theEuropean Union. We identify gaps in currentregulations and their consequences, and discussregulatory efforts that have been undertaken toaddress these gaps. Finally, we describe policyapproaches that could be taken with respect toDTC testing and analyze the merits and draw-backs of such approaches.

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DEFINING GENETIC TESTING

DTC testing has emerged amid a period ofrapid growth in the number of available ge-netic tests. Today, genetic tests for more than1200 diseases are available in a clinical settingand several hundred more are available in a re-search setting (25).

There is no internationally agreed upon def-inition of the term ‘genetic test.’ The term hasbeen defined in various ways in United Statesstate laws, by United States and internationaladvisory committees examining genetic testingoversight (11, 44, 49, 50, 53, 77, 78), and inrecently enacted federal legislation to prohibitgenetic discrimination (28). For the purposesof this review, genetic test refers to an analysisof human DNA, RNA, protein(s), or metabo-lite(s) to diagnose or predict a heritable humandisease; to guide treatment decisions, such asdrug prescribing or dosing on the basis of an in-dividual’s genetic makeup; or to predict diseaserecurrence on the basis of data about multiplegenes or their encoded products (e.g., RNA orproteins).

Over the past decade, genetic testing has be-come integral to diagnosing, predicting, andpreventing disease. Depending on the condi-tion under consideration, genetic testing maybe recommended throughout the life cycle.Preimplantation genetic diagnosis (PGD) fol-lowing in vitro fertilization can identify em-bryos with specific disease-causing mutations,such as Fanconi anemia, or desired genetic char-acteristics, such as HLA type, prior to trans-fer into a woman’s uterus (45). Prenatal testingis performed to detect genetic abnormalities,such as Down syndrome, in a developing fe-tus (26). Newborn screening is performed todiagnose certain metabolic disorders, such asphenylketonuria (PKU), for which early inter-vention can prevent adverse consequences (26).Genetic tests can be used to confirm the di-agnosis of monogenic diseases, such as cysticfibrosis (26), or to determine the risk of devel-oping a particular disease or condition, such ashereditary breast, ovarian, or colon cancer (26).More recently, interest has increased in using

FDA: Food and DrugAdministration

genetic tests to predict response to medication(76), such as Her2/neu testing prior to prescrib-ing the breast cancer drug Herceptin.

With the exception of genetic tests per-formed on samples obtained through invasivemedical procedures (e.g., amniocentesis), anygenetic test could, in theory, be offered directlyto consumers. Although a small fraction of tests,which are available for more than 1500 diseases,are offered in this manner today, there is notechnological barrier to offering a wide rangeof DTC genetic tests, whether diagnostic, pre-dictive, or preventive. Tests offered over the In-ternet include some that are conducted as partof routine clinical practice, such as those formutations that cause cystic fibrosis, hemochro-matosis, and Fragile X syndrome, as well asmany tests that have not yet been accepted intoroutine clinical practice. This is particularly thecase for tests that purport to predict suscepti-bility to common complex conditions, such ascancer and heart disease.

DEFINING DIRECT-TO-CONSUMER

The term ‘direct-to-consumer’ has been usedvariously to refer to both advertising and saleof genetic tests. In the first instance, the avail-ability of a test is advertised to the public, butthe test must be ordered by, and the resultsdelivered to, a healthcare provider. This sit-uation is similar to that seen for prescriptiondrug advertisements in the United States, al-though unlike prescription drugs, the genetictests being advertised are not generally sub-ject to premarket review or approval by theFood and Drug Administration (FDA), as dis-cussed below. Although much policy discussionhas concentrated on advertising, many DTCcompanies appear to be focusing their market-ing budgets on efforts to gain favorable mediacoverage.

In the second instance, genetic tests are notonly advertised directly to consumers, but thepurchase of genetic testing services also is initi-ated at the consumer’s request, and the results

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are delivered directly to the consumer, with-out the involvement of the consumer’s health-care provider. In some cases, the test may be,as a formal matter, “ordered” by a healthcareprovider employed by the company to com-ply with legal requirements, but the company-employed provider does not establish a doctor-patient relationship with the consumer. Thesetwo distinct DTC models have raised differentconcerns.

Direct-to-Consumer GeneticTest Advertising

Few genetic tests are advertised to consumersbut made available only through healthcareproviders. The best-known and most contro-versial example in the United States involvesMyriad’s advertising campaigns for its BRAC-Analysis test, which predicts predisposition tohereditary breast and ovarian cancer. Myriadlaunched a pilot advertising campaign in twocities in 2002 (63, 74) using television, print,and radio to “alert women with a family his-tory of cancer to recent advances in cancer pre-vention and early disease detection” (70). Theadvertising campaign encouraged consumers toconsult their physician about the genetic test.

Several studies have evaluated the impact ofMyriad’s ad campaign on awareness and uptakeof the test, as well as public reaction to the ad-vertising. The resulting data indicate that thecampaign led to increased awareness of testingamong providers and patients, an increase inthe referral rate for genetic counseling servicesamong low-risk women (69), and an increase inthe number of tests ordered (8). The data donot indicate any negative psychological impacton patients or primary care providers as a resultof the ads (69).

In September 2007, Myriad again stirredcontroversy when it launched a larger-scaletelevision, radio, and print advertising cam-paign for its BRACAnalysis test in New York,Connecticut, Rhode Island, and Massachusetts.The ads urged women to discuss their family

history with a doctor or to call a toll-free num-ber to find out if they are good candidates forthe test. Some physicians supported the cam-paign as a means to educate women and primarycare physicians (87). Critics of the campaignraised concerns that the ads may create unnec-essary anxiety and lead to overuse of the test(88).

Direct-to-Consumer Genetic Tests:Models of Provision

The majority of tests advertised DTC also aresold directly to consumers. For example, al-though Myriad does not sell its BRACAnalysistest directly to consumers, the test can be or-dered by consumers directly from a third partycompany, DNA Direct, which employs its ownhealthcare providers, who order the test fromMyriad on behalf of consumers. DNA Directthen communicates the results directly to con-sumers. This marketing scenario demonstratesjust how blurred the lines between DTC adver-tising and DTC sale can become. DTC testinghas also brought about the rise of the third-party intermediary, a company interposed be-tween the patient and the laboratory that makesclaims about the test but does not perform thetesting.

Similar arrangements have been seen inthe United Kingdom; for example, the com-pany MediChecks (65) offers a wide range ofDTC tests via the Internet in collaborationwith the private pathology laboratory TDL.Scienta Health Center (81), a Toronto-basedcompany, offers a range of tests developed andperformed by the Austrian company Genosense(31). Genosense has partners across the globe;for instance, their tests were recently madeavailable in the United Kingdom by a companycalled Genetic Health (27).

Both the number of companies and the va-riety of tests offered have grown since DTCgenetic testing first began. In 2003 Gollustand coworkers (36) identified seven websitesoffering health-related DTC genetic testing

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for seven conditions.1 Of these seven, fourare no longer in business or are no longeroffering DTC testing. Today more than twodozen websites (including three of the originalseven) offer more than 50 health-related tests toconsumers.2

Recent entrants to the sector may augura fundamental change in the size and natureof the DTC genetic testing market (Table 1).Fueled by the diminishing cost of performingDNA microarray analysis and the rapid paceof scientific discovery in genome-wide associ-ation studies, companies in the United States(1, 71) and Europe (12) are offering tests basedon data from very broad panels of SNPs thatprovide information about a variety of commondiseases. These companies, many of which havesignificant venture capital financing and collab-orations with the leading manufacturers of themicroarrays, seek to establish an ongoing rela-tionship with customers by providing periodicupdates on health risk based on new scientificfindings. Some of these companies reportedlyalso are trying to develop large-scale biobanksfor research purposes, and some people havequestioned whether these companies are mak-ing their intentions explicit or appropriately ob-taining informed consent from their customersfor research use of their DNA (35).

Market for Direct-to-ConsumerTesting

Little is known about consumer awareness anduptake of DTC genetic tests. Although DTCtesting companies undoubtedly maintain infor-

1Gollust and coworkers included an additional seven sitesthat either permitted consumers to order tests but requiredresults to be received by physicians, or required consumers toinquire about ordering information. For the purposes of thisreview, neither of these scenarios is considered DTC testing.Of the seven sites that Gollust and coworkers identified inthis category, only two remain active today.2Tests for some conditions, such as cystic fibrosis, are offeredon more than one website. However, because it is not pos-sible to determine which mutations or SNPs an individualcompany is testing for, each test offered by each companywas counted separately to arrive at the estimate of 50 teststotal.

mation regarding the number of consumersusing their services, such information is pro-prietary. Understanding the level of consumerawareness and interest would be useful in con-sidering the need for and appropriate tailoringof policy responses.

A 2007 study by Goddard and coworkers(34) assessed consumer and physician awarenessof nutrigenomic tests and consumer use of suchtests via two national surveys. They found that14% of consumers were aware of nutrigenomictests and 0.6% had used these tests. Consumerswho were aware of the tests tended to be youngand educated with a high income. A greaterpercentage of physicians (44%) were aware ofnutrigenomic tests compared with the averageconsumer, although 41% of these physicianshad never had a patient ask about such tests,and a majority (74%) had never discussed theresults of a nutrigenomic test with a patient.

WHAT IS THE HARM?

The debate about DTC genetic testing occurswithin a broader social and historical context.Clinical genetics arose in the shadow of the eu-genics movement during the first half of thetwentieth century, a dark legacy that under-pins many fears concerning the use and misuseof genetic information (72). In response, theclinical practice of genetics has come to placean immense value on informed consent, confi-dentiality, and nondirectional counseling. Ad-ditionally, clinical geneticists place special im-portance on the act of diagnosis, because manyof the diseases they diagnose are not treatableand therefore require special sensitivity in com-municating test results to patients.

As a consequence of this unique culturaland clinical context, clinical geneticists gener-ally argue that the most appropriate means ofaccessing genetic tests is through a medical con-sultation in which patients receive appropriatecounseling and advice about the suitability ofthe test and its potential implications, expertinterpretation of the test results, and guidanceabout actions to take as a consequence (5, 49).DTC testing challenges this longstanding tenet

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Table 1 Direct-to-consumer (DTC) testing companies

Company Tests offered Delivery model23andMe Susceptibility testing for common diseases as well as ancestry

testingDTC via Internet

Acu-Gen Biolab, Inc. Fetal DNA gender test DTC via InternetConsumer Genetics Fetal gender; caffeine metabolism; alcohol metabolism;

asthma drug responseDTC via Internet

Cygene Direct Osteoporosis; athletic performance; glaucoma and maculardegeneration; thrombosis

DTC via Internet

deCODE (Iceland) Susceptibility testing for cancers, diabetes, heart disease,osteoporosis, and Parkinson’s disease and others; alsoancestry testing

DTC via Internet

Dermagenetics Skin DNA profile; custom skin cream DTC through spas andsimilar retailers

DNADirect (15) α-1 antitrypsin deficiency; Ashkenazi Jewish carrier screening;blood clotting disorders; breast and ovarian cancer; coloncancer screening; cystic fibrosis; diabetes risk; drug responsepanel; hemochromatosis; infertility; recurrent pregnancyloss; tamoxifen

DTC via Internet; geneticcounselors available byphone

G-Nostics (UK) (24) Predisposition to nicotine addiction and response to nicotinereplacement products

DTC via Internet andthrough pharmacies

Genelex Pharmacogenetics testing; celiac disease; hemochromatosis;gum disease; nutritional genetic testing; DNA DietTM

consultation; weight loss system

DTC via Internet

Genetic Health (UK) (Tests areperformed by Austrian testdeveloper and laboratoryGenosense)

For males: genetic predisposition to prostate cancer,thrombosis, osteoporosis, metabolic imbalances ofdetoxification, and chronic inflammation

DTC via Internet; mostservices include a medicalconsultation

For females: genetic predisposition to breast cancer, bonemetabolism (osteoporosis), thrombosis, cancer, andlong-term exposure to estrogens

Nutrigenetic test: test for range of genes that influencenutritional processes such as lipid and glucosemetabolism

Pharmacogenetic test: test for CYP450 genes, which influencehow the liver metabolizes a large number of commonlyprescribed drugs

Premium Male Gene/Premium Female Gene: combine all theother tests except the nutrigenetic one

Geneticom (Netherlands) Common disease risk Not clearGenosense (Austria) Susceptibility tests Do not offer DTC tests

themselves but some of theinstitutions they partnerwith to order tests forconsumers offer DTCtesting (e.g., Genetic Healthin United Kingdom)

(Continued )

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Table 1 (Continued )

Company Tests offered Delivery modelGraceful Earth Alzheimer (ApoE) DTC via InternetHealth TestsDirect

More than 400 blood tests, including a few genetic tests (cystic fibrosiscarrier screen, Factor V Leiden); others may also be available bycalling

DTC via Internet

Health CheckUSA

A wide range of laboratory tests including the following genetic tests:celiac disease; factor V R2; factor V Leiden; hereditaryhemochromatosis

DTC via Internet; as additional service,patient can request interpretation byboard-certified physician; free geneticcounseling offered by Kimball Geneticsfor physicians, patients, and families

Holistic Health Nutrigenomic test: comprehensive methylation panel withmethylation pathway analysis; company also sells a variety ofnutritional supplements

Not described

Kimball Wide range of well-established genetic tests DTC via Internet but detailed telephoneconsultation with certified geneticcounselor is mandatory; report is sent tophysician and customer

MediChecks(UK)

Wide range of well-established genetic tests, from Factor Vthrombosis risk to BRCA testing for breast cancer risk (most tests areperformed by the private pathology laboratory TDL)

DTC via Internet but companyrecommends physician referral forhigh-impact tests such as BRCA

Medigenomix(Germany)

Thrombophilia and osteoporosis risk tests DTC via Internet

Mygenome.com Alzheimer’s disease (genetic testing for common risk factors); drugsensitivities (genetic tests for genes that affect the safety and activityof many common prescription and over-the-counter drugs);cardiovascular disease (genetic tests differentiate treatable risk factorsfor heart disease and stroke); thrombosis (genetic tests identify riskfactors for blood clots); pregnancy risk (genetic tests identify riskfactors for complications of pregnancy); osteoporosis (genetic testsidentify risk factors for osteoporosis and fractures)

Not clear

Navigenics Risk analysis for more than 20 common diseases, such as prostatecancer and diabetes

DTC via Internet

Quixtar Heart health; nutrigenic tests and supplements; also sells dietarysupplement

DTC via Internet

Salugen Nutrigenic tests and supplements DTC sold through spasSciona Heart health; bone health; insulin resistance;

antioxidant/detoxification; inflammationDTC via Internet

Smart Genetics Prediction of HIV progression to AIDS DTC via Internet; free counselingavailable

Suracell DNA profile test that identifies inherited genetic aging profile, and abiomarker assessment test that measures DNA damage, oxidativestress, and free radical levels; personal genetic supplements for DNArepair and nutrition

DTC via Internet

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Clinical validity: theaccuracy with which atest predicts aparticular clinicaloutcome

of clinical genetics. Unsurprisingly, the growthof DTC genetic testing has thus provoked con-siderable concern about the quality of servicethat is provided to patients.

Critics of DTC testing, steeped in the clini-cal genetics tradition, argue that without medi-cal context and qualified counseling, consumersare vulnerable to being misled and to mak-ing inappropriate healthcare decisions. For ex-ample, although mutations in the BRCA1 andBRCA2 genes are highly predictive of breastcancer in women with a strong family history ofthe disease, they do not signal increased risk inwomen with no family history of disease. Ade-quate counseling is needed to explain this con-text, yet the DTC mode of test delivery maymake it difficult to communicate this nuance,particularly because companies have a com-mercial interest in selling tests to the broadestpopulation possible. Inappropriate BRCA-genetesting may lead to needless anxiety or, more se-riously, to women seeking unnecessary medicalinterventions.

However, the change in delivery model fromclinical encounter to consumer transaction isnot the only cause of concern. Some of thenewer genetic tests being offered move beyondtesting for traditional Mendelian disorders—where the presence of certain gene variants ishighly correlated with the development of thecondition—and into the arena of more com-mon complex diseases, where the relationshipbetween specific genetic variants and disease isless clear. An early example was Alzheimer dis-ease, where certain variants in the APOE geneare associated with only a moderately height-ened risk of contracting the disease. More re-cent examples include CYP450 testing to guideselection of antidepressant (selective serotoninreuptake inhibitor) medication, notwithstand-ing expert reports that found a lack of evidencesupporting the clinical validity or utility of suchtesting (17, 60). Other examples include genetictests that purport to predict the risk of diabetes,obesity, and osteoporosis and then make dietand lifestyle recommendations on the basis ofthe results. Many dismiss these claims as pre-mature and not useful to the public (6, 39, 54,

73). Thus, DTC testing raises concerns aboutthe quality of the tests and the associated testingservices.

The rise of DTC genetic testing raises con-cerns about both consumer harms and socialcosts. Potential consumer harms include dis-crimination and stigmatization if the privacyof results is not adequately maintained, in-creased anxiety and needless medical interven-tions based on erroneous or misinterpreted testresults that indicate increased risk of disease,and failure to take preventive measures basedon false reassurance that one is at low risk ofdisease. DTC testing could pose an additionalsocial cost in wasted scarce health resourcesif it leads to unnecessary visits to healthcareproviders and genetic counselors and unneces-sary medical tests and procedures.

Proponents of DTC testing argue that it isa means to increase consumer access to genetictests and to empower consumers to make inde-pendent medical decisions, as well as an oppor-tunity to educate consumers about their ownhealth risks and the steps they can take to mit-igate those risks. There is also an argumentthat some genetic tests pose fewer risks thanothers and that it may be appropriate to of-fer some tests DTC but others not. Argumentsagainst DTC must address the charge of geneticexceptionalism—i.e., the concern that geneticinformation should not be subject to specialregulation that is more stringent than regula-tion that is required of other types of healthcareor health-related information (80). DTC pro-ponents also argue that DTC tests are meetingunmet demand, that there is a public appetitefor information about the fruits of the HumanGenome Project, and that lack of clinical uptakeof new tests can be addressed by DTC advertis-ing and test provision. Furthermore, these pro-ponents argue that it would be paternalistic toprevent individuals from accessing informationabout their genomes (49).

Although these are certainly potential ben-efits of the DTC model, their realizationrequires that DTC testing is offered to the ap-propriate population, performed accurately, in-terpreted correctly, accompanied by adequate

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counseling, and governed by appropriate safe-guards to protect the privacy of the informa-tion. However, as discussed in the next section,the current lack of regulation at all stages of thegenetic testing process precludes the ability tofully assure that DTC genetic testing will ben-efit, rather than harm, the public.

REGULATION OFDIRECT-TO-CONSUMERGENETIC TESTING

Regulation of What?

For genetic testing to benefit an individual pa-tient or consumer, the laboratory performingthe test must be able to get the right answer asto whether a specific genetic variant is presentor absent—so-called analytic validity. The ge-netic variant being analyzed also must correlatewith a specific disease or condition in the pa-tient (i.e., a phenotype) or with heightened riskof disease. This is called clinical validity. Finally,the test must provide information that is help-ful to the individual being tested (e.g., in diag-nosing, treating, or preventing the disease orcondition). The latter is termed clinical utility,and is a somewhat controversial subject amonggeneticists because determining whether infor-mation may be useful to an individual patientcan include subjective considerations, such aswhether knowing the genetic basis for a dis-ease that cannot be treated or prevented maynevertheless provide peace of mind to the pa-tient. Determinations of clinical utility tend tobe made by payers, both public and private, inconsidering whether or not to reimburse fortesting, rather than before a test is offered to thepublic. In the DTC context, the consumer ulti-mately makes the decision about whether takingthe test will be useful, but such a determinationmay be flawed if the information provided bythe DTC company is false or misleading or isnot explained adequately to the consumer.

In the United States and other countries, dif-ferent entities regulate—or foreseeably couldregulate—the analytical and clinical validity ofgenetic tests as well as the claims made about

Analytic validity: theaccuracy with which agiven laboratory testidentifies a particulargenetic variant

Clinical utility: thelikelihood that usingthe test result(s) willlead to a beneficialoutcome

ACGT: AdvisoryCommittee onGenetic Testing

HGC: HumanGenetics Commission

those tests. To date, there is only one exam-ple of a regulatory regime specifically designedto deal with DTC genetic tests. The AdvisoryCommittee on Genetic Testing (ACGT), a gov-ernmental body in the United Kingdom, wasestablished in 1996 for the purpose of consid-ering public health and consumer protection is-sues around genetic testing in both the publicand private sectors (43). The ACGT developeda Code of Practice for genetic testing servicessupplied directly to the public that establishedrequirements regarding informed consent, ge-netic counseling, and provision of informationon the validity and utility of tests to patients inan easily understandable format (3). The Codealso established a system of compliance andmonitoring under which suppliers planning tooffer a DTC genetic testing service (or propos-ing an amendment to an existing service) firstwould present their proposal to the ACGT. Al-though compliance with the Code was volun-tary, companies that did not comply faced thethreat of a statutory alternative.

The ACGT was disbanded in 1999, andits responsibilities were passed to the newlyformed Human Genetics Commission (HGC),the United Kingdom government’s strategicadvisory body on developments in humangenetics. However, after enforcing the Codeonce in the case of the nutrigenetics companySciona, the HGC concluded its position as aregulator was incompatible with its primarymission to offer independent strategic policyguidance to the government; thus the Codeis no longer enforced. In the absence of asystem designed specifically to regulate DTCtesting, regulation of these tests falls underthe existing regulatory mechanisms that coverclinical laboratories, medical devices, and fairtrade and advertising practices.

Regulation of Clinical GeneticTesting Laboratories

Laboratory oversight seeks to ensure the qual-ity of the testing process by, for example, settingrequirements for personnel training, specifyinghow and for what records must be maintained,

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CMS: Centers forMedicare andMedicaid Services

CLIA: ClinicalLaboratoryImprovementsAmendments

and assessing the analytical accuracy of testsperformed by the laboratory. Laboratory over-sight typically includes periodic inspection ofthe facility and its records and also may includeother periodic assessments of quality, such asproficiency testing, which is a means to assessanalytical accuracy. With few exceptions, theentities charged with regulating laboratories donot evaluate the clinical validity of the tests of-fered by the laboratories that they inspect.

United States Regulation

Federal regulation. The United States federalgovernment exercises only limited oversightof laboratories that conduct genetic testing.The Centers for Medicare and Medicaid Ser-vices (CMS) implement and enforce the Clini-cal Laboratory Improvement Amendments of1988 (CLIA) (9). CLIA applies to all clini-cal laboratories that operate or provide test-ing services in the United States. The statutedefines a clinical laboratory as a “facility forthe . . . examination of materials derived fromthe human body for the purpose of provid-ing information for the diagnosis, prevention,or treatment of any disease or impairment of,or the assessment of the health of, human be-ings [9, §263a(a)]. The statute prohibits the so-licitation or acceptance of “materials derivedfrom the human body for laboratory exami-nation or other procedure” unless CMS or aCMS-authorized entity issues the laboratory acertificate [9, §263a(b)].

CMS issued final regulations that imple-mented CLIA in 1992 (64). These regulationscreated “specialty areas” for laboratories thatperform high-complexity tests, which specifiedpersonnel, quality assurance, and proficiencytesting requirements for tests such as toxicol-ogy and immunology. Genetic testing, whichwas in its infancy at the time, was not includedin these specialty areas. As a result, proficiencytesting was never mandated for genetic testinglaboratories.

As awareness grew about the potential roleof genetic testing in healthcare, several ex-pert panels considered what regulatory changes

would ensure the smooth transition of genetictesting from research to practice (53). Keyamong the recommendations of these groupswas that CMS create standards that focusedspecifically on genetic tests (44, 78). AlthoughCMS indicated for several years that it was de-veloping new regulations for genetic testinglaboratories (18), the agency abruptly changedits mind in September 2006 (19). Thereafter,several advocacy groups petitioned the agencyto issue regulations (47), but CMS denied thepetition, citing cost concerns (79).

Inadequate oversight of clinical laboratoriesunder CLIA has harmful implications for DTCtesting (57, 58). Analytical validity is essentialfor accurate test results. Yet the absence of a spe-cialty area means that consumers cannot havefull confidence in DTC tests. Although this istrue for all genetic tests, not just those orderedDTC, the fact that the consumer’s healthcareprovider is not involved in test interpretationincreases the likelihood that analytical errors intesting will not be detected.

Inadequate transparency by CMS also leavesconsumers in the dark about whether the lab-oratory providing results is CLIA certified,has conducted proficiency testing, and/or hasreceived any negative inspection reports; thestatute states that proficiency testing resultsmust be made publicly available, but CMS doesnot have a system for sharing such information.Although CMS does make public informationabout laboratories that have had their certifi-cates suspended or revoked, the most currentinformation is at least two years out of date.

However, even if CLIA was appropriatelyimplemented, it would provide only limited as-surance about the quality of genetic tests. Un-der CLIA, CMS certifies laboratories but doesnot evaluate the clinical validity of the teststhose laboratories offer, instead leaving it up tothe laboratory director’s determination. Thus,although CLIA could, if appropriately imple-mented and enforced, ensure analytic validityof genetic tests (including those offered DTC),CLIA is insufficient to ensure their clinical va-lidity, at least as currently interpreted by CMS.There also is some doubt about whether CLIA

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covers tests that fall somewhere on the bound-ary between clinical tests and so-called lifestyletests.

State regulation. States may choose to followthe requirements of CLIA or to implement asystem of laboratory oversight that is equally ormore stringent. Only the states of New Yorkand Washington have opted out of the CLIAprogram in favor of a state-supervised alter-native. Therefore, laboratories that test sam-ples from patients in New York must be cer-tified and inspected by New York in additionto their inspection under CLIA. Laboratoriesalso may choose to be accredited by a pri-vate accrediting body with higher standardsthan CLIA, such as the College of AmericanPathologists.

State law also dictates whether healthcareprovider authorization is required to obtain alaboratory test, including a genetic test. Somestates explicitly authorize laboratories to acceptsamples from and deliver test results for specifictests (such as cholesterol or pregnancy tests) di-rectly to patients, without authorization from ahealthcare provider. Even when states prohibitDTC testing they may face difficulties in pro-hibiting the sale of DTC tests to consumers intheir state, particularly when such sales are me-diated through the Internet. Other states, suchas New York, categorically prohibit all DTCtesting. Still other states are silent on the is-sue, which leaves it up to individual laboratoriesto decide whether to offer DTC testing. Cur-rently, 25 states and the District of Columbiapermit DTC laboratory testing without restric-tion, whereas 13 states categorically prohibitit (29). DTC testing for certain specified cat-egories of tests is permitted in 12 states; theselaws would likely not permit DTC genetic tests.Even when a healthcare provider’s order is re-quired, the provider may have a conflict of in-terest if he or she is employed by the laboratorythat offers the testing.

European Union regulation. The regulationof clinical laboratories in Europe is similarlypatchy. Although, as discussed below, there have

IVD: in vitrodiagnostic

been efforts to harmonize regulations govern-ing in vitro diagnostic (IVD) devices, as yetno common European requirements for labora-tory quality assurance exist. In part, this may bebecause laboratory testing often is carried outwithin national healthcare services, a sphere ofactivity that is seen as the responsibility of mem-ber states. A recent Europe-wide survey re-vealed that very few laboratories have formal ac-creditation; up to 50% of laboratories surveyeddo not undergo any official inspection (52). Asurvey conducted in 1997 suggested that in Eu-ropean Union countries where clinical genet-ics is well established, often a legal frameworkgoverned the service (40). A more recent sur-vey of European countries found that seven hadlegislation: Austria, Belgium, France, Norway,Sweden, Switzerland, and the Netherlands (33)(Table 2). This legislation often covers the li-censing of laboratories but sometimes relates tothe clinics within which genetics is practiced.

In the European Union, there have beenconsiderable efforts to harmonize oversight oflaboratory quality assurance systems through anumber of national, regional, and internationalschemes, culminating in the European Molec-ular Genetics Quality Network. Participants inthe Network include 34 European countriesand laboratories from Australia and the UnitedStates. These quality assurance initiatives haveled to a broader project, EuroGentest (16), anambitious attempt to move beyond the previousfocus on laboratory quality assurance to developa series of discrete but linked programs that dealwith all aspects of quality in genetic testing ser-vices, from evaluation of the clinical validity andutility of tests to genetic counseling.

In the United Kingdom (and the EuropeanUnion generally), laboratory regulation is notdealt with by statute but through a volun-tary system of accreditation. In the UnitedKingdom, this system is run by Clinical Pathol-ogy Accreditation UK Ltd. (CPA), a body setup by the four main United Kingdom organiza-tions of laboratory professionals and the UnitedKingdom Accreditation Service (UKAS). Lab-oratories that participate in the CPA scheme areinspected every five years. Although the scheme

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Table 2 European legislation governing genetic testing

Country RegulationsAustria Gene Technology Act 1994 requires that labs that conduct predisposition and carrier status testing must be accredited;

tests for diagnosis are exempt.Belgium 1987 legislation stipulates that genetic diagnostic testing can be carried out only in the country’s well-established

genetics centers and with the provision of genetic counseling; state funding is provisional on the supply of detailedannual activity reports.

France Legislation passed in 2000 states that testing can be done only by accredited personnel and labs and sets downguidelines that cover the reporting of results and confidentiality of records.

Norway 1994 act covers accreditation of institutions; it sets no restrictions on diagnostic testing but requires counseling forpredictive, presymptomatic, and carrier-status testing and outlaws such testing on individuals 16 and under.

Netherlands Legislation limits genetic testing to those institutions with a government license and places restrictions on commercialgenetic testing.

Sweden 1988 act states that genetic testing can be carried out only with the permission of the National Board of Health andWelfare.

is voluntary, the majority of United King-dom clinical laboratories participate. Withinthe National Health Service (NHS), all localpathology services are expected to be accred-ited by CPA or the equivalent, a requirementthat includes NHS genetic laboratories (13).Membership in the recently established UnitedKingdom Genetic Testing Network also re-quires compliance with new European guide-lines, evidence of internal quality control, andparticipation in external quality assessment.

With the exception of human immuno-deficiency virus (HIV) testing, the UnitedKingdom has no restrictions on patients order-ing DTC medical tests. The HIV Testing Kitsand Services Regulations of 1992 made it an of-fense to sell, supply, or advertise for sale an HIVtesting kit or a component part to a member ofthe public. In 2002, the Dutch government in-troduced regulations to restrict the availabilityof some tests so that they could be accessed onlythrough doctors or pharmacists.

Regulation of Genetic Testsas Medical Devices

IVD genetic tests fall, at least in theory, un-der the broader statutory regimes for the reg-ulation of medical devices. These regimes arefar less onerous than those for pharmaceuticalproducts, but they nevertheless share the goal of

ensuring safety and effectiveness through a va-riety of regulatory mechanisms, including pre-market review and regulation of labeling andpromotional materials. Ensuring truth in la-beling and truthful promotion—an honest ac-count of the strengths and weakness of a test’sperformance—can be thought of as the funda-mental function of premarket review. For high-risk tests the process may be more difficult. Reg-ulators set out in some detail the types of clinicalstudies required to gain approval. Once a deviceis on the market, it is subject to postmarketingsurveillance and to removal from the market-place if it is found to be unsafe. However, asdiscussed below, although genetic tests are as aformal matter considered to be medical devices,for the most part they have been subject to farless regulation than other devices.

United States regulation. Currently, theFDA regulates test kits sold to clinical laborato-ries to perform testing pursuant to its authorityto regulate IVD devices (55). Both genetic andnongenetic laboratory tests are considered tobe IVDs if the components of the tests are bun-dled together, labeled for a particular use, andsold to a laboratory as a unit. Such kits must un-dergo successful premarket review before theymay be commercially distributed. The amountand type of evidence that the FDA requiresdepend on the specific claims made by the test

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manufacturer. The FDA has to date reviewedapproximately eight test kits that detect variantsin human DNA or DNA expression products(55).

However, most genetic tests are developedin-house by clinical laboratories and do notuse a test kit. These laboratory-developedtests (LDTs) use purchased individual com-ponents and/or components the laboratoriesmake themselves. The FDA has historically ex-ercised “enforcement discretion” with respectto LDTs. As a result, the FDA does not reviewthe vast majority of genetic tests, and in partic-ular does not assess clinical validity (55).

The FDA recently indicated its intention torequire premarket review for a limited subsetof LDTs known as in vitro diagnostic multivari-ate index assays (IVDMIAs) (22). IVDMIAs areLDTs that analyze laboratory data using an al-gorithm (an analytical tool) to generate a resultfor the purpose of diagnosing, treating, or pre-venting disease. The agency expressed height-ened concern about these LDTs because theyuse proprietary methods to calculate a patient-specific result that cannot be independently de-rived, confirmed, or interpreted by a healthcareprovider. The FDA cleared its first applicationfor an IVDMIA in February 2007. The test an-alyzes gene expression products (mRNA) to de-termine the likelihood of breast cancer return-ing within five to ten years of a woman’s initialcancer diagnosis (23).

Most genetic tests sold directly to consumersare LDTs and few, if any, would be consideredIVDMIAs. Thus, most DTC genetic tests soldare not subject to any independent oversightto assure their clinical validity. Consumers of-fered these tests therefore have no means to dis-tinguish those tests that have been shown to beuseful in diagnosis or prediction of disease fromthose that lack adequate scientific support forthe claims being made. Additionally, the FDA’sability to regulate claims about medical prod-ucts is predicated on its regulation of the prod-ucts themselves. When the FDA approves a testkit, it can also constrain the claims that can bemade about a test’s benefits and mandate thedisclosure of information about a test’s limi-

Laboratory-developed test(LDT): testdeveloped for in-houseuse by a clinicallaboratory

IVDMIA: in vitrodiagnostic multivariateindex assay

tations or risks. In the absence of FDA over-sight of LDTs, the agency has no mechanismto address false or misleading claims made bycompanies that sell DTC tests. As discussed be-low, a bill was introduced in the United StatesCongress in 2007 that would give the FDA ex-plicit authority to regulate LDTs; however, asof the time of publication of this review the billhas not yet passed.

International Regulation

Other countries have taken varying approachesto LDT oversight. In the European Union,Sweden, and Australia, LDTs are included indevice regulations (although there are exemp-tions in the European system for what aretermed health institutions). In Canada, de-vice regulators have sought legal opinion onwhether they can regulate LDTs and have re-ceived a succession of conflicting opinions, themost recent of which suggests that such testscannot be regulated as medical devices undercurrent law.

Although Europe treats commercial LDTsas devices subject to the IVD Directive, it is notclear that this applies to LDTs performed bylabs outside of Europe. For instance, the UnitedStates companies InterGenetics and Myriadhave both made their tests available throughthird parties in the United Kingdom. TheseUnited Kingdom third parties collect the sam-ples and return the results, but the test is per-formed in the United States. Both the UnitedKingdom regulator and the European Com-mission appear to consider such companies tobe exempt from the IVD Directive. This is theopposite of the approach taken in the UnitedStates; a reference laboratory based in Europewould need FDA approval to market its test inthe United States.

Although the European system treats LDTsas medical devices, most genetic tests neverthe-less are not subject to independent premarketreview in the European Union (42). This is be-cause they are classified as low-risk and there-fore exempt from review by an independentthird party. In contrast, the United States,

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Table 3 Risk Classification

Country/region Risk categories∗ Genetic tests Premarket reviewUnited States I–III II or III YesCanada I–IV III YesAustralia I–IV II or III Yes (class III)Europe I–III I No

∗I = low risk, II = moderate-low risk, III = moderate-high risk, IV = high risk.

FTC: Federal TradeCommission

GAO: GovernmentAccountability Office

Canada, and Australia classify genetic tests thatfall within the medical device regulations asmoderate- to high-risk, and therefore gener-ally require premarket review (Table 3). Thus,although Europe does not suffer the confusionover the regulatory status of LDTs that prevailsin the United States, it still does not review ge-netic tests, including those sold directly to con-sumers, before they are marketed.

Regulation of Claims

In addition to laws that regulate medical de-vices, laws that prohibit false or misleading ad-vertising claims could ensure that consumersreceive accurate information. In the UnitedStates, Europe, and elsewhere, general lawsgovern the misleading promotion of goods andservices and can be enforced either through pri-vate complaints to the courts by individuals orthrough the actions of statutory bodies, such asthe Federal Trade Commission in the UnitedStates and the Office of Fair Trading in theUnited Kingdom. However, these mechanismsby and large have not been used to prohibit falseand misleading claims about DTC genetic tests.

United States

Federal Trade Commission. The FederalTrade Commission (FTC) Act declares unlaw-ful “unfair or deceptive acts or practices in or af-fecting commerce” and directs the Commissionto prevent such activities (21). The statute alsospecifically prohibits the dissemination of falseadvertising to induce the purchase of drugs, de-vices, food, or cosmetics and defines the phrase“false advertisement” as “misleading in a mate-rial respect.” The statute directs the agency to

take into account not only representations madefor the product, but also omissions of facts thatare material given such representations.

To the extent that companies offering DTCgenetic tests make claims of clinical validitywithout adequate scientific evidence, the FTChas the legal authority to bring an enforcementaction to prohibit such claims from being made.However, the FTC has not pursued enforce-ment action against companies that make falseor misleading claims about genetic tests evenwhen it has received complaints about a spe-cific test. The agency did, however, issue a con-sumer alert warning the public to be wary ofthe claims made by some companies, and advis-ing that some results have meaning only in thecontext of a full medical evaluation (20).

Congress. The United States Congress also hasthe power to conduct investigations and hear-ings to uncover unfair and deceptive trade prac-tices. In 2006, the Senate Special Committeeon Aging held a hearing (85) concerning a re-port by the Government Accountability Office(GAO) regarding companies that offer nutri-genetic tests over the Internet (86). The GAOinvestigated four such companies by submit-ting DNA samples along with fictitious con-sumer profiles and analyzing the reports pro-vided by the companies. The GAO found thatalthough all four companies stated their testswere not intended to diagnose disease or pre-disposition to disease, all sent back results warn-ing that the fictitious customers were at risk fora range of medical conditions, including type2 diabetes, osteoporosis, cancer, heart disease,and brain aging. These predictions appeared tobe independent of which DNA sample was sentin and which gene variants were present in the

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sample. The GAO also reported that several ofthe companies sent recommendations for “per-sonalized” dietary supplements, which in real-ity contained ingredients similar to multivita-mins that could be purchased in the drugstore,but that cost much more. Some of the claimsfor the supplements also were unproven, suchas the claim that they could “promote DNArepair.”

Following the Senate hearing, the FDA sentletters to several of the investigated companiesexpressing concern that their activities mightbe subject to FDA regulation, and requestinga meeting (38). It is unclear what subsequentlytranspired; however, these companies continueto offer their DTC tests.

States. State laws in the United States also pro-hibit unfair or deceptive trade practices withintheir borders, and these laws could be broughtto bear on false or misleading claims about ge-netic tests. To date, these laws have not beenused against any DTC test manufacturer. How-ever, in the wake of Myriad’s most recent cam-paign, the Connecticut attorney general issueda subpoena for information from the companyon the basis of concern about the accuracyof some of the company’s advertising claims(75).

Europe. The regulation of test claims inother countries varies, but instruments includevoluntary advertising codes, statutes, and regu-lations. In the United Kingdom, the Medicines(Advertising) Regulations 1994 (SI 1932)appears to prohibit the advertising of DTCtesting services (66, Regulation 9). However,the Medicines (Advertising) Amendment Reg-ulations 2004 (SI 1480) amended the previouslaw and removed the prohibition on advertisingover-the-counter medicinal products for thediagnosis of genetic disorders to the public(68). Still, the Advertising Standards Authority(ASA) (2) enforces a code of practice thatrequires that advertisements be “legal, decent,honest and truthful” and “capable of objectivesubstantiation.” Special rules apply to healthproducts.

ASA: AdvertisingStandards Authority

The ASA’s powers were tested in 2003 whenthe HGC’s Genetic Services subgroup com-plained about a product being sold by theGrowth Hair Clinic (Genetic Hair). The ASAupheld the HGC’s complaint that the adver-tisement implied that the product used genetictechnology for hair restoration/grafting whenin fact no such technology exists (43).

Although the ASA enforces a voluntarycode of practice, promotional claims also aregoverned by statute, in particular the TradeDescriptions Act (84). Under the Act, it is anoffense for a person to apply a false (to a ma-terial degree) or misleading trade descriptionto goods or services. The Act was tested in2004 when the nongovernmental organizationGeneWatch UK complained about claims madeby g-Nostics regarding the NicoTest. Gene-Watch was told that the Act did apply, and thecomplaint was passed to the Trading Standardsoffice in Oxford (local to g-Nostics). Shortlyafter GeneWatch filed its complaint, g-Nosticsmodified its website claims regarding NicoTest.Thus, GeneWatch did not pursue its complaint(Personal communication with Helen Wallace,Director, GeneWatch UK).

Private Law Mechanisms

The judicial system also serves as a nonregula-tory means to deter false or misleading claimsthat cause physical or financial harm to con-sumers. Whether in practice the threat of lia-bility would deter false or misleading claims forDTC genetic tests is unclear. The consumerwould first need to be aware that he or she wassubject to false or misleading claims, and wouldhave to demonstrate harm resulting from thoseclaims. For example, the consumer would needto show that the test result led to some harm-ful action, and that the action was a foresee-able result of the misleading information. Emo-tional harm, such as added anxiety from beingtold one was at greater likelihood of develop-ing a disease, would likely be an insufficientbasis for receiving damages in the absence ofmore concrete injury. However, financial harmas a result of misstatements could be sufficient,

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and in fact is at the heart of the only lawsuitfiled against a DTC test company so far. InFebruary 2006, a class action lawsuit was filedagainst Massachusetts company Acu-Gen Bio-labs for its Baby Gender Mentor test (56). Thelawsuit, which was filed on behalf of womenwho had used the test and were dissatisfied withthe incorrect results received, focused on thecompany’s failure to honor its “200% moneyback guarantee” and its claim of “99.9% accu-racy.” In addition, the lawsuit claimed that thecompany provided incorrect medical advice towomen about the health of their fetuses, whichcaused them emotional distress and led them toundergo unnecessary testing (5).

Private law mechanisms could—at least intheory—function in other countries as well.However, it is widely acknowledged that suchconsumer law mechanisms have significant lim-itations. In general, only a very small propor-tion of consumers with grievances pursue com-plaints against companies. The reasons for thisinclude consumers’ lack of appreciation of theirlegal rights, consumers’ lack of resources (time,money, and the skills or experience to pur-sue legal claims), the limited number of legalfirms practicing consumer law, and lack of ac-cess to experts able to provide evidence to sup-port complaints (82).

PENDING LEGISLATIONAND RECOMMENDATIONS

The year 2007 was marked both by a significantincrease in the range of tests and test providersin the DTC testing market and by a renewal ofthe policy debate about the oversight of genetictests in general and DTC genetic tests in partic-ular. In the United States, two bills were intro-duced in Congress to strengthen governmentoversight over genetic tests, including thosesold DTC. The Laboratory Test ImprovementAct, introduced by Senator Edward Kennedyand Senator Gordon Smith, would grant ex-plicit authority to the FDA to regulate LDTsas medical devices (62). DTC tests would haveto undergo FDA review before being marketed.The Genomics and Personalized Medicine Act

of 2007, introduced by Senator Barack Obamaand Senator Richard Burr, would direct theDepartment of Health and Human Services(DHHS) Secretary to improve the safety andeffectiveness of genetic tests (30). Under thisbill, the Secretary would be required to com-mission a study from the Institute of Medicinethat would make recommendations regardingthe development of a “decision matrix” for usein determining which tests to regulate and howthey should be regulated [30, §7(b)(3)]. The billwould direct the Centers for Disease Control tostudy the issue of DTC testing and its impact onconsumers. The prospect for passage of eitherof these bills is uncertain.

In addition to these legislative efforts, theSecretary’s Advisory Committee on Genetics,Health, and Society (SACGHS), which advisesthe DHHS Secretary on genetics policy issues,was asked by Secretary Michael Leavitt to pro-duce a report on the oversight of genetic testsas part of his Personalized Healthcare Initiative(14). A draft report was issued for public com-ment in November 2007, and the final reportwas issued in April 2008 (77) (Table 1).

In the United Kingdom, the HGC pub-lished in 2007 More Genes Direct, a reportthat revisits the recommendations the Com-mission made in 2003 about the regulationof DTC genetic tests (50). Whether or notthe government will respond remains to beseen, but the HGC now intends to facilitatethe development of a code of practice, andother actions may be taken at a Europeanlevel. A revision of the IVD Directive is saidto be imminent, and there is much expecta-tion that it will become more prescriptive andplug some of the current regulatory gaps, inpart to address concerns about genetic tests(7, 61). As part of the Global HarmonizationTask Force (GHTF), European regulators havebeen involved in the development of a newmodel for risk classification and conformity as-sessment of IVDs, which, if adopted by Europe,would see many new genetic tests subject to in-dependent premarket review (32).

Another European body, the Council ofEurope, also is driving policy in this area. In

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2007, it published a draft Protocol on GeneticTesting that would require most genetic test-ing to be performed only “under individualizedmedical supervision.” The impact of the Pro-tocol will depend on how many states chooseto formally ratify it and thereby accept it as alegally binding protocol.

Finally, in Australia the Therapeutic GoodsAdministration (TGA), the body responsiblefor licensing IVD devices, is revising its regula-tions, in part as a response to concerns expressedby successive Australian governments about theregulation of genetic tests. The TGA intendsto implement regulatory mechanisms that willprohibit access to home use tests (self-testing)for serious disease markers, including genetictests. As part of this process, the TGA has is-sued a guidance document about the regulationof nutrigenetic tests (83) (See SupplementalTable 1. Follow the Supplemental Materiallink from the Annual Reviews home page athttp://www.annualreviews.org).

POLICY APPROACHES

Since the early 1990s, numerous expert bod-ies have convened to consider the oversightof genetic testing generally and, in recentyears, DTC genetic testing specifically. Thesegroups, typically established by the govern-ment, have issued myriad reports and rec-ommendations (Table 1). Notwithstandingthese prodigious efforts, little has actuallychanged in the oversight of genetic testing,while the number and range of tests has risendramatically.

There is a wide range of possible policy ap-proaches to DTC genetic testing—from pro-hibiting the sale of all such tests to permittingthem without limitation. Policymakers mustdecide if the risks posed by DTC genetic testsrequire a targeted approach, or whether existingregulatory frameworks are adequate and ade-quately enforced. Policymakers also must con-sider whether greater control over the DTCtesting market would be best achieved throughenhanced regulation of the quality of genetictests more broadly, or whether there are addi-

tional risks raised by DTC genetic tests thatrequire distinct regulatory approaches.

Between the two extremes of a total banand an unfettered market lies the intermedi-ate option of permitting certain tests to be soldDTC by certain entities under certain condi-tions. For example, in its Genes Direct report,the Human Genetics Commission laid out anapproach that would limit the sale of DTC ge-netic tests to a subset of tests considered appro-priate to be offered without medical referral.Other restrictions that could be put in placeinclude demanding that entities offering DTCtests meet licensure and quality control require-ments, and insisting on heightened scrutiny(e.g., premarket review) of tests marketed di-rectly to consumers.

Limitations also could be placed on DTCadvertising, such as prior review of advertise-ments to ensure accuracy, limitation of adver-tising to certain types of tests and certain typesof media (e.g., print and Internet versus televi-sion and radio), and requiring the disclosure ofcertain information in advertisements. Any re-strictions on advertising would need to be con-sistent with a particular country’s legal protec-tions of commercial speech.

Some of these policy options may be pur-sued by enhancing the enforcement or scope ofexisting regulatory instruments; others mightrequire new mechanisms, such as the ACGT’sCode of Practice. Such codes could be devel-oped by a group of companies or a trade associ-ation and voluntarily adopted, or could be de-veloped and enforced by a government agency.As in the case of the Code of Practice, the gov-ernment also can threaten to impose mandatoryrequirements if companies do not adhere to avoluntary code (39, 40, 82).

CONCLUSION

DTC genetic tests continue to proliferate whilepolicies to ensure their quality have lagged be-hind. Establishing a coherent oversight systemis challenging because of the different entitiesinvolved in oversight, the lack of existing reg-ulations tailored to the DTC testing context,

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and the lack of agreement about the need forand type of oversight appropriate for DTC tests(41). The heterogeneity of tests offered and therange of delivery and promotional models fur-ther complicate the development of oversightmechanisms. The challenge for policymakers isto create standards that adequately protect con-sumers from harms associated with unsafe tests,while ensuring access to tests that are analyti-cally and clinically valid in a manner that pro-

vides appropriate context and counseling. Reg-ulatory requirements must be proportionate tothe risks posed by the tests, and must recognizethat some tests carry greater risks than others.

It is unlikely that we will see the emergenceof a common, harmonized approach to DTCtesting. However, efforts to strengthen over-sight of genetic testing generally, which are un-derway in many countries, will, it is hoped, im-prove the quality of DTC genetic tests.

SUMMARY POINTS

1. The range of companies and tests in the direct-to-consumer (DTC) market is growingand seems likely to continue to increase.

2. Clinicians, scientists, consumers, and patient groups have raised concerns about variousaspects of the DTC testing market.

3. DTC genetic testing is subject to a complex overlapping series of regulations, but thereare significant gaps in the existing regulatory systems in both Europe and the UnitedStates.

4. A succession of policy reports have called for enhanced oversight of genetic tests ingeneral and DTC genetic tests in particular, but thus far there has been limited policyaction.

FUTURE ISSUES

1. The recent high-profile launch of a number of new consumer genetics companies hasheightened concerns, as have renewed efforts to advertise DTC tests.

2. These developments have been matched by a renewed interest in oversight among poli-cymakers, but it remains to be seen what action will result.

DISCLOSURE STATEMENT

The authors are not aware of any biases that might be perceived as affecting the objectivity of thisreview.

ACKNOWLEDGMENTS

The Genetics and Public Policy Center is supported at The Johns Hopkins University by ThePew Charitable Trusts and with research funding from the National Human Genome ResearchInstitute.

Some of the research informing this paper was conducted by Stuart Hogarth and David Melzerwith funding from the Wellcome Trust. The Trust played no part in the writing of this paper orthe decision to submit it for publication.

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Annual Review ofGenomics andHuman Genetics

Volume 9, 2008Contents

Human Telomere Structure and BiologyHarold Riethman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

Infectious Disease in the Genomic EraXiaonan Yang, Hongliang Yang, Gangqiao Zhou, and Guo-Ping Zhao � � � � � � � � � � � � � � � � � � �21

ENU Mutagenesis, a Way Forward to Understand Gene FunctionAbraham Acevedo-Arozena, Sara Wells, Paul Potter, Michelle Kelly,

Roger D. Cox, and Steve D.M. Brown � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �49

Clinical Utility of Contemporary Molecular CytogeneticsBassem A. Bejjani and Lisa G. Shaffer � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �71

The Role of Aminoacyl-tRNA Synthetases in Genetic DiseasesAnthony Antonellis and Eric D. Green � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �87

A Bird’s-Eye View of Sex Chromosome Dosage CompensationArthur P. Arnold, Yuichiro Itoh, and Esther Melamed � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 109

Linkage Disequilibrium and Association MappingB. S. Weir � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 129

Positive Selection in the Human Genome: From Genome Scansto Biological SignificanceJoanna L. Kelley and Willie J. Swanson � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 143

The Current Landscape for Direct-to-Consumer Genetic Testing:Legal, Ethical, and Policy IssuesStuart Hogarth, Gail Javitt, and David Melzer � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 161

Transcriptional Control of SkeletogenesisGerard Karsenty � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 183

A Mechanistic View of Genomic ImprintingKy Sha � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 197

Phylogenetic Inference Using Whole GenomesBruce Rannala and Ziheng Yang � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 217

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Transgenerational Epigenetic EffectsNeil A. Youngson and Emma Whitelaw � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 233

Evolution of Dim-Light and Color Vision PigmentsShozo Yokoyama � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 259

Genetic Basis of Thoracic Aortic Aneurysms and Dissections: Focuson Smooth Muscle Cell Contractile DysfunctionDianna M. Milewicz, Dong-Chuan Guo, Van Tran-Fadulu, Andrea L. Lafont,

Christina L. Papke, Sakiko Inamoto, and Hariyadarshi Pannu � � � � � � � � � � � � � � � � � � � � � � � � � � � 283

Cohesin and Human DiseaseJinglan Liu and Ian D. Krantz � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 303

Genetic Predisposition to Breast Cancer: Past, Present, and FutureClare Turnbull and Nazneen Rahman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 321

From Linkage Maps to Quantitative Trait Loci: The Historyand Science of the Utah Genetic Reference ProjectStephen M. Prescott, Jean Marc Lalouel, and Mark Leppert � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 347

Disorders of Lysosome-Related Organelle Biogenesis: Clinicaland Molecular GeneticsMarjan Huizing, Amanda Helip-Wooley, Wendy Westbroek,

Meral Gunay-Aygun, and William A. Gahl � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 359

Next-Generation DNA Sequencing MethodsElaine R. Mardis � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 387

African Genetic Diversity: Implications for Human DemographicHistory, Modern Human Origins, and Complex Disease MappingMichael C. Campbell and Sarah A. Tishkoff � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 403

Indexes

Cumulative Index of Contributing Authors, Volumes 1–9 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 435

Cumulative Index of Chapter Titles, Volumes 1–9 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 438

Errata

An online log of corrections to Annual Review of Genomics and Human Genetics articlesmay be found at http://genom.annualreviews.org/

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