testing

Blaine Bettinger (the Genetic Genealogist) writes that some commercial test offerings are trying to sort out a way to tell you how Neandertal you are:

Once [the Max Planck] study came out, I knew it was only a matter of time before companies began offering tests that examined the percent of Neanderthal contribution to a test-taker’s genome.

This is one of the stickiest places to be a blogger. Bettinger links to a testing company's information on its product (including promotion of "Neandertal themed art" for the customer, sold at their Las Vegas gallery). Others have linked to Bettinger, drawing more attention.

I think that as a scientist, more promotion is the last thing I should be giving this company. So I won't be naming or linking to their advertising.

Ironically, the promotional material does not make any false statements of fact. The material makes it perfectly clear that the product does not test any gene variants that scientific research has shown may have come from Neandertals. Instead, the product reports on gene variants that we don't know about from Neandertals.

Huh?

You may wonder how a company can market such a product as a "Neanderthal Index". Since "Neanderthal Index" is not a scientific concept, a company can claim whatever it wants.

So what is it? According to the material, the Neanderthal Index is computed from (a very few) STR alleles shared with "archaic" populations. Those "archaic" populations aren't Neandertals, they're Basques, Turks, Syrians, and other living people. Anthropologists do not call these people "archaic", so this is not a scientific concept either. Nobody has demonstrated that the listed populations are more or less Neandertal-like than any other living people. Most of the differences between these living populations emerged during the last 10,000 years.

You'd do better putting calipers on your skull and measuring your cephalic index. At least that would tell you whether some real phenotype is Neandertal-like.

I don't imagine that customers beating down the doors for this product. I think it exists as a way of bringing attention -- Neandertals are in the headlines. That's a big reason to not give them any attention. The test has nothing whatsoever to do with Neandertals as we scientifically understand them.

Can you tell that I'm disgusted by this?

Here in my lab, we're in a very good position to say that no test today can accurately report on your individual proportion of Neandertal ancestry. Until we have characterized a broader set of gene trees than we have so far, we are really not able to give any answer about how similar any person's genome is to Neandertals. We can't say yet how heterogeneous the human population is today in its ancestry from different parts of the world during the Late Pleistocene. For the past thirty years most working geneticists completely ignored the possibility of such heterogeneity, we are only just beginning to investigate it seriously.

This kind of thing may not be why the FDA is looking to regulate personal genomics. Neandertal ancestry is not directly relevant to health. But if customers buy tests like this thinking that they are learning about Uncle Thag, just how much misinformation will they accept from other tests that purport to tell them something more important?

I wrote about the UC Berkeley genetic testing of incoming freshmen earlier this spring. The summer is halfway over and the saliva kits have been sent. Now Scientific American has a long and balanced article on the contrasting approaches to genetic testing at Berkeley and an upper-level seminar at Stanford: "Exposing the Student Body: Stanford Joins U.C. Berkeley in Controversial Genetic Testing of Students".

This is an article worth reading by anyone interested in personalized genomics or bioethics. I wouldn't have expected that university classes would be such an early battleground for genetic information, privacy rights, and junk science. But nothing about either program is unprecedented. I wrote in 2005 about genetic testing associated with a course at Penn State. As I noted in 2005, I have a lot of concerns about applying these genetic tests to students. They can have an educational effect, but not always a beneficial one.

The UC-Berkeley program actually provides vastly less information than the ancestry testing that has been applied to students in courses in the past. That's my main objection -- it's an awful lot of trouble for essentially no scientific value. I mean, they might as well just do blood types!

There's a lot in the article about the thinking of the main decision makers. I'll share these two paragraphs:

In fact, after Salari originally proposed the class last fall, a Stanford task force of about 30 basic scientists, clinical scientists, genetic professors, genetics counselors, bioethicists, legal counselors and students spent several months working through the various ethical issues and establishing safeguards to protect students. In contrast, the organizers of Berkeley's project incurred criticism because they spent hardly any time considering the potential reaction to their new orientation program.

Kimberly Tallbear, a professor of science, technology and environmental policy at Berkeley, explains that neither [Dean] Mark Schlissel nor any of the project's other organizers consulted with Berkeley's bioethics community. "Schlissel said several times they were surprised about the controversy," Tallbear says. "I said to him, 'Well doesn't that tell you that you needed input from us? Because we could have told you about the controversy and debate.'"

The article also discusses the "research study" aspect -- participants will be asked to sign an informed consent form and data will be kept. It may seem like the three genotypes provided to the students would not be very interesting as research topics. But it's not too hard to imagine psychology grad students in three years becoming very interested in research projects involving a high-risk population for binge drinking and known ALDH2 genotypes. Berkeley freshmen may be enrolling now in the first phase of a long-term research study on alcohol and sexual assault.

Amy Harmon returned to the NY Times last weekend with a story about the court settlement between Arizona State University and the Havasupai tribe ("Indian tribe wins fight to limit research of its DNA").

The story explains the details of the case well -- in 1990, geneticists started taking samples for research on the causes of diabetes; samples were stored and later applied to other research questions, some of which were objectionable to the tribe's members.

I'm quoting the following passage at length, because it really shocked me when I read it:

But a few years later, a graduate student using new technology came up with a way to discern variations in the Havasupai DNA, which was stored in a university freezer, and he wrote a dissertation based on his research.

Carletta Tilousi, one of the few Havasupai to attend college, stopped by Professor Martin’s office one day in 2003, and he invited her to the student’s doctoral presentation.

Ms. Tilousi understood little of the technical aspect, but what she heard bore no resemblance to the diabetes research she had pictured when she had given her own blood sample years earlier.

“Did you have permission,” she asked during the question period, “to use Havasupai blood for your research?”

The presentation was halted. Dr. Markow and the other members of the doctoral committee asked the student to redact that chapter from his dissertation.

Wow. Talk about a horrifying situation, for both students. The doctoral student clearly shouldn't have been given the samples. Harmon continues to describe the subsequent events and investigation, giving a picture of the importance of education bringing information into these communities.

Dan Vorhaus gives some additional perspective on the settlement, from a legal perspective. He discusses the legalities of informed consent and how those have been refined over the years. He also touches on the Personal Genome Project strategy of complete openness -- which he speculates might itself fall victim to future technological developments.

Also last week, Anne Buchanan touched on the issue of stored samples and informed consent. In "The fierce non-controversy", she describes the disposition of James Neel's DNA samples from the Yanomamo Indians of Brazil, and the long process of arranging for their repatriation. Some are in Ken Weiss' lab at Penn State, and Buchanan describes the political and practical problems that remain to be resolved:

One issue is that, as we do every sample that comes through our lab, we have treated these bloods as potentially biohazardous. Not because we know anything specific about these samples that would, after 50 years, make them still potentially harmful, but because we always err on the side of caution. The samples have been deep-frozen so that some pathogens could in principle have survived. Since we don't know what will be done with the bloods once they are back in Brazil, this is something that Ken has discussed with every official who contacts him about their return. We are currently still waiting to hear from the Brazilian embassy how best to ensure they are safe and delivered to the proper recipients in Brazil.

Meanwhile, in spite of the fact that this is a non-issue, as these bloods will be returned when the logistics are worked out, and that has always been true, agreed to by all those labs that currently house such samples, for years an American anthropologist has masterminded numerous online letter writing campaigns to stir up undergraduates who are not properly informed about what's been going on, to demand the repatriation of these bloods.

Again, we see how it makes a difference who has information and how they get that information to relevant communities. There is much more in the post and it provides a very good companion to Harmon's piece, if you're thinking of students.

The National Institutes of Health directorate this week announced the creation of a new database for tracking and providing public information about commercial gene tests:

The National Institutes of Health announced today that it is creating a public database that researchers, consumers, health care providers, and others can search for information submitted voluntarily by genetic test providers. The Genetic Testing Registry (GTR) aims to enhance access to information about the availability, validity, and usefulness of genetic tests.

Currently, more than 1,600 genetic tests are available to patients and consumers, but there is no single public resource that provides detailed information about them. GTR is intended to fill that gap.

It is hard to tell much from the press release, but I think it foreshadows two significant aspects of the registry. First, the NIH seems to be entering the realm of quality control:

GTR genetic test data will be integrated with information in other NIH/NCBI genetic, scientific, and medical databases to facilitate the research process. This integration will allow scientists to make, more easily and effectively, the kinds of connections that ultimately lead to discoveries and scientific advances.

This would enable NIH to provide an independent summary of whether test markers correspond to clinical studies. Second, the registry seems to be encouraging active engagement of companies in the process:

During the development process, NIH will engage with stakeholders — such as genetic test developers, test kit manufacturers, health care providers, patients, and researchers — for their insights on the best way to collect and display test information. In addition, other federal agencies, including the Food and Drug Administration and the Centers for Medicare and Medicaid Services, will be consulted.

I'm not sure what this means for the possible regulation of tests in the future. The engagement of the FDA at this point may presage greater involvement of the agency in genomic testing. The involvement of Medicare in the database seems more important, as the federal government will likely become the largest purchaser of genetic testing in the near future.

In relation to the Medicare/Medicaid involvment, I discussed candidate Obama's record on gene testing in 2008 ("Good only for entertainment value... and, of course, the government"). At that time, the main concern was standardization of records:

Providing diagnostic value for SNP screens or genome sequences will take a massive effort at standardizing information about joint gene-phenotype associations. Direct-to-consumer gene testing companies presently differentiate themselves based on the different information they provide to their customers. That approach works as long as there is little of value in the results -- the companies today are succeeding or failing on the basis of the communities of customers they are building, with the stories of customers providing the best advertisements. That's the nutrition supplement market.

But that approach will start to fail if genetic tests start to allow serious risk mitigation in health maintenance. If two companies provide divergent information to customers, in a way that impacts the customers' interactions with their physicians, I expect that the outcome will be some massive lawsuits and further federal regulation. If the government becomes the health care purchaser -- and with Medicare it already is the largest -- we can expect to see early federal intervention in this market, focused upon standardizing genetic information provided to physicians.

The creation of an NIH registry may reflect growing surveillance of the different interpretive results from these tests, with an eye toward future government purchasing protocols.

The new registry announcement is discussed in more detail by Dan Vorhaus at Genomics Law Report: "Evaluating the NIH’s New Genetic Testing Registry. " He gives some background relating to the 2008 report “U.S. System of Oversight of Genetic Testing” (PDF), commissioned by the Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS) during the Bush Administration. As Vorhaus points out:

Although the SACGHS report acknowledged that “short-term voluntary approaches” to test registration might be appropriate, it also clearly indicated that the fundamental objective was the creation of a permanent and mandatory test registry.

This important distinction has not been lost on others. In a press release celebrating the GTR, the advocacy group Genetic Alliance (whose founder, Sharon Terry, has been one of the most outspoken advocates for a mandatory registry, including making the case several months ago in this very space) applauded the NIH’s announcement while simultaneously looking forward “to the registry becoming mandatory so that we are all apprised of the quality and availability of genetic testing across the nation.” (links in original)

Probably the most important element is the involvement (for now, at the level of consultation) of Medicare. Companies that want a piece of that market will be more or less compelled to join the registry:

Depending on the degree to which purchasers of genetic tests come to rely on the GTR, inclusion in the GTR may well become a de facto requirement for any commercial genetic test provider, even if it is not converted into a legal requirement.

In the place of "purchasers" read "Medicare". And of course insurance companies have similar incentives to require tests that participate in the registry.

(via Collective Imagination blog, and Genetic Future)

I'm attending a symposium on genetics and genealogy of the African Diaspora this morning. Fatimah Jackson is here giving a very interesting talk about her genetic work in Africa and African-Americans, and in particular her idea of "ethnogenetic layering" (Jackson 2008), which is basically a strategy for describing the fine-scale makeup of present-day populations by examining their genetic ancestry from different regions of the Old World.

Part of her research has involved characterizing the regional distribution of mtDNA haplotypes within African populations. She shared some newer data with us, but I thought it worth pointing people to an earlier publication by Bert Ely, Jackson and others (2006), which gave rise to some strong insights about the poverty of current sampling of African populations.

The study reports on a sample of 3725 mtDNA sequences (HVS-I) from a diversity of sub-Saharan African populations. That's quite a massive sample of sequences, certainly on the scale that had been available earlier. It is substantially more numerous than

When a sample of 74 Gullah/Geechee mtDNA sequences were compared with the sub-Saharan database, approximately half of the mtDNAs were identical to two or more mtDNAs in the database and only seven mtDNAs matched mtDNAs from a single ethnic group. The remaining 28 mtDNAs were not identical to any sequence in the expanded database.

Similar results were obtained when the 97 African-American AFDIL mtDNAs were compared with the databases. Approximately half (49) of the mtDNAs were identical to multiple sequences in the original database. As with the Gullah/Geechee sample, fewer than 10% of the sequences matched a sequence from a single ethnic group, and 40% of the sequences did not have any perfect match in the database (Ely et al. 2006:3).

There are two aspects worth noting in those results. On the one hand, the common haplotypes -- the ones that the African-American samples were likely to have a match to -- were not regionally specific within Africa. They are shared by many ethnic groups, distributed across the continent.

On the other hand, 40% of the African-American sequences have no match among the nearly 4000 sequences taken from continental Africa. That's astounding to me, just from the standpoint of sampling. Most of the common haplotypes will emerge within a relatively small sample, so to find something you haven't already seen, you have to sample disproportionately more -- in fact, exponentially more -- individuals. You can just imagine how many tens or hundreds of thousands of sequences you would have to gather to have an adequate representation of African mtDNA for this purpose -- the purpose of finding matches for a large fraction (say, more than 90 percent) of African-American mtDNA haplotypes that originated in Africa (there are of course a substantial fraction whose recent maternal ancestry originated somewhere else).

One of the features of the symposium is a discussion of the relevance of ancestry testing. Jackson is an expert in this field and well-recognized -- she appeared in several of the "African-American Lives" episodes, for example.

With several companies and organizations now offering various kinds of ancestry tests, these have become increasingly affordable. But the results are often confusing; people don't know how to interpret them. Some of that confusion was evidenced in questions here at the symposium -- as part of a year-long discussion group, several local people submitted cheek swabs for ancestry interpretation. The results are often poor, because the sampling of recent populations is inadequate to really answer many questions. Where were today's populations 300 years ago? Have we adequately sampled the variation of present populations.

Research like Jackson's has shown that even widespread and numerous samples provide a real poverty of information about mtDNA diversity. The situation is vastly worse if we turn to autosomal variation, because the samples are smaller and more scattered.

Of course, for many anthropological purposes, the samples we have today are tremendously useful. My work on recent selection, for example, has made leaps and bounds on samples of a few hundred individuals.

But the converse case -- you take a person and ask whether you can diagnose their origin -- that task requires much larger samples to gain any statistical confidence in the general case. There may be specific haplotypes that are highly specific as to their present distribution -- but then, all of those are rare haplotypes, and you have to be lucky enough to have it within the comparative sample that the organization or company has gathered.

I'm still listening here and some of the later presentations will touch on the issues of genetic ancestry testing more directly. But I thought I would share a quote I really liked, with which Jackson ended her comments:

I'm not against genetic ancestry testing. It's fun. But in the final analysis, you have to look in the mirror, and you decide who you are.

Related posts:

Skip Gates discovers that genetic tests don't mean what he thought they meant.

Anne Wojcicki from 23andMe comments on genomics and race

Unintended consequences of genetic ancestry tests

References:

Ely B, Wilson JL, Jackson F, Jackson BA. 2006. African-American mitochondrial DNAs often match mtDNAs found in multiple African ethnic groups. BMC Biology 4:34. doi:10.1186/1741-7007-4-34

Jackson FLC. 2008. Ethnogenetic layering (EL): an alternative to the traditional race model in human variation and health disparity studies. Ann Hum Biol 35:121-144. doi:10.1080/03014460801941752

A couple of weeks ago, the Texas Tribune reported on an investigation of the archiving of blood samples taken from newborn infants: "DNA Deception".

For decades, the state has screened newborns for a variety of birth defects, pricking their heels and collecting five drops of blood on a paper card. Until 2002, the cards were thrown out after a short storage period. But starting that year, the state health department began storing blood spots indefinitely, for “research into causes of selected diseases.” Four years later, DSHS began contracting with Texas A&M University’s School of Rural Public Health to warehouse the cards, which were accumulating at a rate of 800,000 a year. State health officials never notified parents of the changes; they didn’t need consent for the birth-defect screening, so they didn’t ask for it for research purposes. The agency’s rationale was that it let parents who asked opt out of the newborn blood screening and de-identified all of the samples before shipping them off (emphasis added).

So much for informed consent. "We're from the government, and we're here to help you."

The state was sued by parents last year and rapidly settled the lawsuit before pre-trial discovery. Now, it is suspected that the state was trying to avoid drawing attention to some of the uses of the blood samples -- including several hundred which were used to develop a forensics database of mtDNA variants.

E-mails indicate that in 2003, when the agency started to release blood spots for outside research, officials knew they had a parental consent issue on their hands — but tried to avoid it. When a researcher proposed a project, the director of birth defects monitoring wrote that he’d “prefer to not have to go through” the process of getting consent. Another agency official responded that parents "never consented for blood spots to be used for research. … On the other hand, I believe [the health department] already uses (deidentified?) blood spots for some research, so that might not be a big deal.”

All states now test for metabolic disorders in newborns; the tests require only a blood spot on treated paper. The National Newborn Screening and Genetics Resource Center has more information on the specific tests and a very up-to-date list by state. It is amazing to me, as someone who has had four kids in the last ten years, just how quickly these screening programs became universal.

It is therefore hard for me to believe that Texas is going to be an exception. Surely we'll discover that some other states are archiving these blood samples instead of destroying them? Checking them out to researchers for no-consent research?

Science gives us a "policy forum" this week on gene doping. The lead author, Theodor Friedmann, is the chair of the "Gene Doping Expert Group" at the World Anti-Doping Agency.

The essay describes the current potential of gene doping, and is a good short review. I found the paragraphs on "marketing gene doping" very interesting:

Athletes are an especially vulnerable population in the marketing of performance enhancement (31). Reputable athletes or coaches with little knowledge of genetics are at a disadvantage in assessing "scientific" claims that appear in advertisements. Marketing is particularly worrisome when the science is still a work in progress, when a person's health can be adversely affected, and when consumer knowledge about genetics is low. Although advertisements promoting products that promise to enhance athletic performance have pervaded the Internet for many years, recently it has become home for advertisements that promote products to "alter muscle genes...by activating your genetic machinery" (32), or that state "your genetic limitations are a thing of the past!" (33) or "Finally, every bodybuilder can be genetically gifted!" (34).

These are people who make easy targets for nutrigenomics and other questionable areas of "health enhancement." A large number of amateur bodybuilders and fitness enthusiasts create a "gray market" supporting questionable products, and these products themselves support the ecosystem of effective performance enhancement drugs. They also create a lot of biochemical noise for those who want to find new tests for performance enhancers.

The essay includes a few paragraphs that describe the prospects of future detection of gene doping. It may be very difficult. Detecting some synthetic performance-enhancing agents requires the cooperation of primary producers, who add tracers to their products. Gene doping might enhance performance for periods months or years after the vector is administered, and may not require dosage that would significantly alter isotopic or chemical signatures, even if they contained such tracers. The authors suggest that the incidental biochemical effects of gene doping might enable the identification of a "signature" of such products:

For instance, exposure of murine myoblasts to IGF-1 has been shown to induce transcriptional and proteomic changes that may eventually constitute a "signature" specific for exogenous IGF-1 exposure (29, 30). Of course, the application of these kinds of global assays would require rigorous validation of a connection with specific doping agents or methods.

I am very skeptical -- it's likely that the "signature" of a doped individual will not differ appreciably from the normal variability of tissue metabolism, particularly in the subset of high-performance athletes. Still, it may be possible to find one particular tissue type that provides a high-information-content message about normal versus doped processes. I just think that a lot of innocent athletes are likely to get snared in this net as it closes in on clinical validation.

References:

Friedmann T, Rabin O, Frankel MS. 2010. Gene doping and sport. Science 327:647-648. doi:10.1126/science.1177801

I complained mightily about the problems I had getting George Church's essay ("The Genome Generation"). Church is the major organizer of the Personal Genome Project, and advocates the idea that individuals should release their genetic information to the public.

In his essay, Church begins by pointing to the coming benefits of genetic research, refers to the need to support the "altruists" who provide their information openly for research, and ends by making a generic call for genome sharing:

As "the first genomic generation" we will set the rules that many future generations may follow. Will we treat our genomes like our faces, which we share publicly even though they reveal details about our health, ancestry, and personality? Or will we be forced to hide them from view?

Talk about a leading question! Will you remain hidden behind your genetic burka?

I'll ask a different leading question: Is it generally a good idea to release your personal information to the internet?

Naturally, it depends on the information. And how other people will use it. We know that credit card numbers can be used by bad people for nefarious purposes. Book purchases can be used by Amazon to market more books to you. And your recently played iTunes list can be used by major movie studios to determine whether you would be a good unpaid crowd marketer.

Church's argument relies on two assumptions:

1. Someone with your genetic information can't hurt you.

2. You will benefit along with the rest of humanity from open genome sharing.

Of course, assumption 2 is subject to the classic free rider problem -- why share when the collective benefits will come to you anyway? So that brings us back to assumption 1.

Presently, there are few practical ways to hurt a person using her genome. Of course, that depends on the meaning of "hurt". Some people would be extremely embarrassed to reveal aspects of their ancestry, which is easily exposed with genome information. In fact, the second public genome (Watson's) was almost immediately subjected to ancestry testing. These testing results were publicized in an apparent attempt to discredit Watson's public statements on race.

In the United States, it sadly quite common to investigate the ancestry of political candidates, and to use ancestry to discredit candidates' public statements. Without question, the world would be a better place if total openness would make people value diversity, as Church hopes. But I doubt that unilateral genomic openness will inspire such a sunny outcome.