testing

In Erika Check's Nature article on celebrity genomes, she includes a passage in which Francis Collins points out a problem with public access to private genomes:

But it's not clear that all of the genome pioneers are acting altruistically. Watson said at the Cold Spring Harbor meeting on 10 May that he has not asked either of his grown sons for permission to publish his genome sequence, which 454 has said will be publicly posted in some form. That has raised questions about the responsibility of sequenced individuals to family members who share their DNA.

"This will be a challenging question, because if you're planning to put this information in a truly open database, there are issues of risk not just to you, but to your relatives," Collins says. "Jim clearly felt those risks were not such as to cause him to take action on them."

Putting your genome information online is not only about you: it includes half the genome of each of your children, half the genome of your parents, a fourth that of your grandchildren, nieces, and nephews, and so on.

I wrote about this problem two years ago, linking to a New Scientist article that described how a young man had tracked down his biological father -- using DNA samples put online by the man's relatives.

The boy paid FamilyTreeDNA.com $289 for the service. His genetic father had never supplied his DNA to the site, but all that was needed was for someone in the same paternal line to be on file. After nine months of waiting and having agreed to have his contact details available to other clients, the boy was contacted by two men with Y chromosomes closely matching his own. The two did not know each other, but the similarity between their Y chromosomes suggested there was a 50 per cent chance that all three had the same father, grandfather or great-grandfather.

OK, so this particular situation must be pretty rare. But it is a good example of a case where a parent and child may have divergent interests with respect to genetic information. On the obvious level, the son wants to discover his father's identity while the father may want to conceal it. On the not-so-obvious level, a grandfather may want to find children that his son may have fathered, irrespective of the father's wishes. The father in question might even be dead, might have specified in his will his wishes for all sperm donations to remain private, but a grandfather can easily circumvent those wishes through the simple expedient of publicizing his DNA profile.

Families with inherited genetic conditions are already dealing with these privacy issues, such as mothers who don't want a Huntington's test and daughters who get it anyway, revealing the mother's status (my post earlier this year, referring to Amy Harmon's NY Times article). Whole-genome scans for most people will not reveal the same, tragic, level of risk, but will generate hundreds of smaller questions -- like a load of tiny skeletons-in-the-closet.

This week in Science, Collins and coauthor William Lowrance expand on the problem. Their "Policy Forum" article notes existing U.S. federal law and regulations concerning personal data and the problems that genomic information is likely to generate in the current legal context.

Until recently, most genomic research used data and biospecimens obtained fairly directly, from the data subjects themselves or clinical repositories or specialized research collections. This will continue, as it has many advantages. But now, in efforts to increase the range and quantity of data, large-scale research platforms are being built that assemble, organize, and store data, and sometimes biospecimens, and then distribute these to researchers (see figure). The advantages of such platforms, in addition to scale, are that they can be a robust staging-point for screening data quality, fostering uniformity of data format, and facilitating analysis. Some platforms accumulate data directly (as the Framingham Heart Study does); others assemble them from a variety of sources (as The Cancer Genome Atlas, the Genetic Association Information Network, and the Wellcome Trust Case Control Consortium do and U.K. Biobank will) (7). Among the design and governance issues are whether and how to de-identify the data and at what stages to conduct scientific and ethics review.

These new data flows, genomewide analyses, and novel arrangements such as the Informed Cohort scheme recently proposed by Kohane et al. (8) are relatively uncharted territory with respect to human subjects and privacy considerations. Precedent doesn't provide sufficient guidance. For example, the Human Genome and HapMap Projects have geno-typed DNA from only a few hundred carefully selected people who prospectively consented to the analysis and to open publication after thorough explanation, discussion, and community consultation. The projects have been scrutinized closely all along. But when the data relate to more people (by orders of magnitude) or to retrospective analysis of biospecimens, then for pragmatic reasons such painstaking selection, consent negotiation, and scrutiny can't generally be achieved (Lowrance and Collins 2007:600).

The article does not really arrive at any conclusions about what should be done -- Lowrance and Collins limit themselves to a fairly dry listing of potential problems and conditions leading to them. Throughout, they emphasize the reliance of the current regulations on "de-identification" -- that is, the removal of most identifying information from sequences or samples. Under today's U.S. guidelines, data that have had identifying information removed may be used quite broadly without further consideration of human subjects protections:

Construal of genomic "human subject." If data have been de-identified but include large amounts of genetic information, are the individuals still considered "human subjects"? The answer has important implications for consent, ethics review, and safeguards. McGuire and Gibbs have urged that "genomic sequencing studies should be recognized as human-subjects research and brought unambiguously under the protection of existing federal legislation" (22), but this could be unnecessarily extreme. In the United States, the Office of Human Research Protections considers that data or biospecimens collected for one purpose but then key-coded and used secondarily for research are not "individually identifiable," and therefore the research is not human-subjects research (7). This is a strong incentive to support de-identification and to de-identify data (Lowrance and Collins 2007:602).

Lowrance and Collins mention that "de-identification" is by no means as simple as applied to substantial parts of genomes, particularly when accompanied by phenotypic data such as redacted medical histories. Routine data-mining techniques would be sufficient to identify individuals within medical research studies; matching individual genome profiles to a name may be accomplished without need to match data to a "key" if the information is unique enough.

I favor the protection of individual privacy over greater research access to research data, particularly since DNA sampling and data retention by governmental agencies has become increasingly routine. In a post directly before her Personal Genome Project Q&A, Hsien-Hsien Lei wrote "Police want to collect abandoned DNA from everyone," noting that UK police will soon have authority to collect DNA with the same legal standing as trash -- if you throw it away, it's not private. We have to assume that governments will keep multiple databases of DNA barcodes for people, that these will include other personal information, and that they will be insecure. One may argue that most of the privacy threat actually comes from these other databases, and that personal genome information adds relatively little. Nevertheless, it would be better to add nothing at all, or to generate new models accentuating security.

Since I've been thinking about information theory a lot lately, I can't help but think that some kind of cryptographic solution should be applied -- so that nobody can read a person's sequence data without her private key. A person might choose to opt-in to research studies or other projects that require genotyping data, but still the sequence would be secured by encryption.

The objection to such an approach is that large-scale, long-term studies of health attributes require samples of many thousands -- even tens or hundreds of thousands of people. Today, these datasets are routinely deindividualized and dispersed around the world to researchers involved with many different projects. There is little chance of centralized control over this information after it is dispersed -- and Lowrance and Collins describe the potential problems with changing the system. With so many participants, the genotype data are a tempting target for black-hats. Any very large-scale study, in which hundreds of researchers have access to deindividualized data, there are many chances for unscrupulous researchers to steal information or put it in situations where theft by outsiders may occur.

But practices can be implemented to reduce the risk of data loss or theft. For one thing, the main reason why those studies need so many participants is because they are waiting for people to have rare adverse health events, and don't want to wait so long for results. So they really only need to know genotype data for the small group of people who have these conditions. If decryption is restricted to such small groups of study participants, the risk of unauthorized data access would be greatly reduced.

No system is perfectly safe, but in this case the agglomeration of data from thousands or millions of individuals in single databases leads to risks that scale nonlinearly with database size. So reducing the size of data chunks available to any one person may be a significant protective step.

References:

Lowrance WW, Collins FS. 2007. Identifiability in genomic research. Science 317:600-602.doi:10.1126/science.1147699

Check E. 2007. Celebrity genomes alarm researchers. Nature 447:358-359. doi:10.1038/447358a

A few months ago, a particularly egregious neighbor dog left a gift on our lawn -- while my fascinated girls watched out the window. Naturally, I ran outside, shooed off the dog, used a plastic bag to pick up the steaming pile, and knocked on the neighbors' door. I think I interrupted the neighbor kids from their Playstation or something; in any event, the visits from the big brown dog abated for a while.

Now, Hsien-Hsien Lei tells me that technology may help with future dog-related problems:

Perhaps the animal control officers in Port Phillip, Australia would be able to help me out. They're being provided DNA kits for cases where a dog has attacked a human or a pet. They'll be collecting DNA evidence from fur, saliva, blood, and excrement. In 2004, the first Australian animal mauling case to use DNA evidence resulted in two dogs being destroyed for killing a Pomeranian. Their owner was fined $7,244.

Yes, it sounds more serious when you think of attacks or bites. No, I don't suppose too many people will spring for a DNA test on a fecal sample. But those poochie pyramids make me pretty irate -- and we have a toddler running around the yard who treats the local pine cones and rocks like a tasting bar!

Before we knew where our dog pest lives, we had to do the Nancy Drew thing to find out -- we just followed it one day. But now, a less spry person with a little cash to spare could just stock up on some tissue collection darts and set up a blind.

Oh, so what? That's not how you hunt dogs?

This is from the Nicholas Wade article on James Watson's genome:

Some scientists believe that it will be medically useful to sequence patients' genomes when the cost of sequencing falls to around $10,000 or less. Dr. Egholm said that with improvements already under way, the 454 sequencing machine would soon be able to sequence a human genome for $100,000. The cost of sequencing has been dropping so fast in the hands of groups like 454 Life Sciences and Solexa Inc., a subsidiary of Illumina Inc., that some technologists predict the $10,000 genome will be attained in a few years.

Doesn't $10,000 seem like an interesting price point? I've written a couple of times about the idea of $1000 whole-genome sequencing. Here's what I wrote last year:

My question is, why are they shooting for $1000? It seems to me that if you can go from $2.2 million to $1000, it won't take very much longer to go to $100, or even less. The materials cost and computational resources certainly won't cost that much in volume.

They are framing the cost in terms of the cost of a personal computer, but it wasn't so long ago that the "accepted" cost of a PC was over $3000, and now most buyers spend a lot less than $1000. So that's arbitrary too.

My guess is that the magic $1000 figure that keeps getting quoted is an attempt to prime insurers to expect that billing amount when the process becomes common. The question is not how much you would pay for a genome, but how much an insurance company would pay on your behalf. A lot of diagnostic procedures approach that billing amount, so it is a convenient pricing hook.

If I'm right, then you can place the $1000 genome in the same category as MRI scans and X-rays, neither of which is priced at what it is worth in materials or energy, but in terms of amortization of equipment and expert interpretation.

But $1000 won't be practical for quite a long while. So what are the implications of the $10,000 genome?

Remember that most young people just don't care very much about their genomes. Here's what I found of my students in 2005:

The results: only two would pay more than the price of a CD, around $16.00. Most didn't want the information at all --- they didn't see what possible use it could have for them.

In contrast to my undergraduates, an insurer would probably find a $1000 genome pretty useful, particularly for current customers. That's too expensive for screening potential clients, but well in the price range of procedures that they normally cover.

$10,000, on the other hand, is not in the usual range of diagnostic procedures. We have to think about what would make a genome worth that much more than a typical diagnostic procedure. It seems pretty obvious that you would only pay that much for a procedure if it had the potential of preventing something much more expensive. But for this much money, it can't be a mere long-term potential, it must be an immediate potential.

So we are looking for medical bills far in excess of $10,000 that would be prevented by a genome sequence. Read that carefully: bills that would be prevented, not diseases that could be cured.

It seems like the main application of a $10,000 genome sequence would be to prevent people from having expensive surgeries, particularly transplants.

Suppose you are an insurer that might normally approve a $250,000 transplant surgery, with a 30 percent failure rate. For $10,000, suppose you could gain some better prediction of long-term survival or organ rejection rates. So you implement a required whole-genome screening before approving surgery, and require that the patient's genetic "risk" factors don't exceed some threshold. If you eliminate 10 percent of surgeries, your investment in whole-genome sequencing yields a 250% return -- assuming the cost of care without surgery approximates that after failed surgeries.

Now, I have my doubts about whether this scenario will come to pass. For one thing, SNP screening is going to be a lot cheaper than whole-genome sequencing for a long time, and probably will be just as informative. The benefit of the whole-genome sequence -- that it finds the rare variants that no one else has -- also makes it much less medically useful, since nobody knows what your unique rare variants actually do.

AP reporter Matt Crenson has a story on the "twisted path" of one man's DNA-aided search for his biological father.

Nobody ever told [Martin] Marshall how to approach people to ask for their DNA. Nobody ever explained how to tell a complete stranger that maybe, just possibly, the man who raised him — the man who played catch with him in the yard, who taught him to drive, who sent him off to war and welcomed him home — may have cheated on his mother.

"What are the procedures," Marshall asks. "Where's the handbook for how you go about doing this kind of research?"

The story goes through Marshall's search for his father from the very beginning, leading down several dead-end trails and failed attempts at DNA matches. The last one is the most poignant -- both because he tries the hardest to make it happen, and because of the result.

I linked to a similar story earlier this month. A few people e-mailed me, letting me know that reporters had been frequenting genealogy mailing lists looking for stories -- which aren't, of course, characteristic of most people's experiences.

What I like about the current story is that it illustrates both positives and negatives. Marshall received helpful advice and cooperation from genealogy groups and many possible relatives, but at the same time became so attached to his quest that one possible relative felt he was being "stalked". The story gives enough detail to understand both Marshall's point of view and the opposite perspective.