Many ques­tions still unan­swered over per­sonal ge­nomics

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The se­quenc­ing of the hu­man genome has led to faster and more ef­fi­cient ap­proaches to ge­nomic anal­y­sis and the emer­gence of di­rect-to-con­sumer ge­netic tests. As a re­sult, some have en­vi­sioned that an in­di­vid­ual’s genome soon will be an in­te­gral part of the med­i­cal record, along with fam­ily his­tory, life­style and other per­sonal de­scrip­tors. Be­fore that goal is re­al­ized, how­ever, there are a num­ber of ob­sta­cles to be over­come, in terms of tech­ni­cal and clin­i­cal util­ity, cost-ef­fec­tive­ness, reg­u­la­tion and eth­i­cal con­sid­er­a­tions.

First, the clin­i­cal util­ity of genome-wide as­so­ci­a­tion stud­ies has not been ad­e­quately demon­strated for most com­mon dis­eases. In gen­eral, re­search will need to ex­pand to in­clude pop­u­la­tions other than Euro­peans and to ad­dress rare ge­netic vari­ants rather than—or in ad­di­tion to—the com­mon ones cur­rently as­sessed. As re­cently as Au­gust, re­searchers iden­ti­fied sev­eral tech­ni­cal chal­lenges fac­ing next-gen­er­a­tion se­quenc­ing.

Also, per­sonal ge­nomics does not take into ac­count nonge­nomic data, such as diet, ex­er­cise, epi­ge­net­ics or ex­po­sures to en­vi­ron­men­tal stim­uli. In­deed, the few stud­ies that have sought to as­sess whether ac­cess to ge­netic in­for­ma­tion has an im­pact on per­sonal health be­hav­iors have shown lit­tle change in life­style be­hav­iors af­ter re­port­ing of ge­netic test re­sults.

Fi­nally, for­mal eval­u­a­tions of ge­nomic tests have not demon­strated a wide­spread clin­i­cal util­ity. The Cal­i­for­nia Technology As­sess­ment Fo­rum eval­u­ated four ge­netic tests and found that two of them failed to meet cri­te­ria of safety, ef­fi­cacy and im­prove­ment in health out­comes. One ex­pert re­cently told a Govern­ment Ac­count­abil­ity Of­fice in­ves­ti­ga­tor that “the most ac­cu­rate way for these com­pa­nies to pre­dict dis­ease risks would be for them to charge con­sumers $500 for DNA and fam­ily med­i­cal his­tory in­for­ma­tion, throw out the DNA, and make pre­dic­tions based solely on the fam­ily his­tory in­for­ma­tion.” Af­ter a year­long in­ves­ti­ga­tion, the GAO demon­strated that com­pa­nies such as 23andMe, Nav­i­gen­ics, Path­way Ge­nomics and De­code Ge­net­ics of­fered mis­lead­ing and in­con­sis­tent risk es­ti­mates to their clients. The GAO ac­cused 10 of the 15 com­pa­nies it in­ves­ti­gated of en­gag­ing in “de­cep­tive mar­ket­ing, mis­in­for­ma­tion and ques­tion­able prac­tices.”

It also is im­per­a­tive that the costs of not only DNA se­quenc­ing but also of the en­tire ge­netic test­ing en­ter­prise de­crease sub­stan­tially be­fore the technology is widely adopted. In­fra­struc­ture is needed to in­te­grate ge­netic in­for­ma­tion with other health data. Ac­cord­ing to ge­nomic pi­o­neer Craig Ven­ter, “We don’t have the com­pu­ta­tional in­fra­struc­ture to com­pare even thou­sands of geno­types and phe­no­types with each other,” let alone the vastly larger dataset en­vi­sioned for health­care set­tings. We also will need ex­cep­tion­ally good in­for­ma­tion ag­gre­ga­tors and fil­ters to sift through the enor­mous amounts of data gen­er­ated by whole genome se­quenc­ing.

If use­ful in­for­ma­tion can be gained at a rea­son­able cost, then health­care providers will need train­ing to in­ter­pret these data, and pay­ers will need to de­vise new ways of re­im­burs­ing clin­i­cians for dis­cussing ge­netic in­for­ma­tion with pa­tients. More­over, knowl­edge of sup­posed ge­netic risks could drive up other health­care costs, in­cit­ing a “cas­cade ef­fect” of un­war­ranted fol­low-up di­ag­nos­tics and in­ter­ven­tions. Thus, even if a genome can be se­quenced for $1,000, it prob­a­bly will not be clin­i­cally use­ful un­less thou­sands of ad­di­tional dol­lars are spent in in­ter­pre­ta­tion.

The reg­u­la­tory en­vi­ron­ment of per­sonal ge­nomics is in flux. It is un­clear whether the Food and Drug Ad­min­is­tra­tion will ap­prove lab­o­ra­tory-de­vel­oped tests, as ev­i­denced by the con­tro­versy sparked in May of this year, when Wal­greens an­nounced its pro­posal to sell Path­way Ge­nomics test kits di­rectly to con­sumers; the drug­store even­tu­ally dropped the pro­posal.

Fur­ther­more, there is con­cern that ac­cess to ge­netic in­for­ma­tion may lead to dis­crim­i­na­tion, and that the Ge­netic In­for­ma­tion Non- dis­crim­i­na­tion Act of 2008, while a step in the right di­rec­tion, still has loop­holes, for ex­am­ple in life in­surance and pre-ex­ist­ing con­di­tions. States such as New York and Cal­i­for­nia have sent letters to di­rect-to-con­sumer ge­netic test­ing com­pa­nies re­quir­ing that all ge­netic tests be re­quested by physi­cians, align­ing with re­cent Amer­i­can Med­i­cal As­so­ci­a­tion rec­om­men­da­tions that ge­netic test­ing be con­ducted only un­der the su­per­vi­sion of a “qual­i­fied health­care pro­fes­sional.”

The limited clin­i­cal util­ity demon­strated by per­sonal ge­nomics raises a num­ber of im­por­tant eth­i­cal con­sid­er­a­tions. At the heart of the mat­ter is a ten­sion be­tween an in­di­vid­ual’s right to know his or her own ge­netic in­for­ma­tion and the in­for­ma­tion de­liv­erer’s obli­ga­tion to do no harm. It is im­per­a­tive, then, to clar­ify the re­spon­si­bil­i­ties di­rect-to-con­sumer com­pa­nies have to their clients.

This re­la­tion­ship is in be­tween a physi­cian-pa­tient re­la­tion­ship, in which the physi­cian has a duty to “do no harm,” and a fee-for-ser­vice mar­ket trans­ac­tion, in which the con­sumer is as­sumed to have in­formed him­self of the rel­a­tive risks and ben­e­fits and there­fore has the free­dom to buy the ser­vice. In ei­ther re­la­tion­ship, the ser­vice provider must be a qual­i­fied pro­fes­sional, and it is un­cer­tain— es­pe­cially in light of the GAO find­ings— whether the di­rect-to-con­sumer com­pa­nies’ em­ploy­ees meet ba­sic re­quire­ments of ge­netic or health­care coun­sel­ing.

Fi­nally, as with all ge­netic test­ing, reg­u­la­tors will need to con­sider how to pro­tect the relatives of the in­di­vid­u­als un­der­go­ing test­ing. The re­sults of one’s own ge­netic ex­plo­ration nec­es­sar­ily have im­pli­ca­tions for the mem­bers of his or her fam­ily. Di­rect-to-con­sumer com­pa­nies, and in­deed all pro­fes­sion­als in­volved in the dis­clo­sure of ge­netic in­for­ma­tion, will need to ad­dress whether a “duty to warn” ex­ists in this con­text as it does in the clin­i­cal set­ting.

Rapid ad­vances in ge­netic anal­y­sis and se­quenc­ing tech­nolo­gies have gen­er­ated en­thu­si­asm for the trans­la­tion of ge­nomic dis­cov­er­ies into the health­care set­ting, ush­er­ing in what some have termed the “age of per­son­al­ized medicine.” Weak­nesses ex­ist, how­ever, in the reg­u­la­tory frame­works and cost-ben­e­fit mod­els sur­round­ing the new technology and the im­pact it will have on pa­tient care. Ques­tions about ef­fec­tive­ness, cost, le­gal­ity and ethics will need to be an­swered be­fore we truly wel­come this new age.

Mil­dred Cho is di­rec­tor and Maya Wolpert is pro­gram man­ager of the Cen­ter for In­te­gra­tion of Re­search on Ge­net­ics and Ethics at the Stan­ford Uni­ver­sity School of Medicine, Palo Alto, Calif.

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