David Dobbs helpfully reviews the past few weeks of Marc Hauser-related revelations:
Overall, I think this replication is a wash in terms of its impact on Hauser’s larger issues. Some will see some redemption here, others more sin. I suspect those will cancel out and that Hauser will stand or fall on the rest of the record, which appears to remain pretty damning.
Dan MacArthur reads the American Medical Association's letter to the FDA about direct-to-consumer genetics testing, and doesn't like what he sees ("American Medical Association: You Can’t Look At Your Genome Without Our Supervision").
In other words, the AMA is seeking to maintain its members’ traditional monopoly over the interpretation of genetic information – and they expect regulators to act as their enforcers, beating down the upstart DTC genomics companies who have wandered onto their sacred turf.
This is, of course, an absurd, desperate demand. If doctors think that people should consult them about their genomes, they shouldn’t run crying to the regulators to provide the necessary force; instead, they need to convince the public that a medical consultation adds genuine value to their genomic information. Unfortunately for the AMA, right now it’s far from clear that this is true: in many cases, DTC genomics customers are far better equipped to interpret their results than their doctors are.
Seems to me they're taking more or less the same approach with direct-to-consumer genomics as they did with Doc Brinkley's goat gland operations. (Just to be clear, not a good reaction.)
Razib takes the point and concludes that Brinkley's Mexican radio model -- that is, offshore sequencing and genotyping -- will probably win the day. Still, maybe it's time for a data rush before somebody pulls the regulatory plug ("Run as fast as you can"):
But here’s the important point, I’ve got the markers on several computers and in Gmail. Once the information is out, it’s out. There’s no way that the government can put the genie back in the bottle for those of us who have raced ahead of feared regulation. So run, just in case. Once you cross the threshold they can’t drag you back, no matter how powerful their lobbyists and marketers are.
I'm thinking it would be notably helpful if we came up with a more useful application of nuclear SNP data to genealogy. Hard to regulate away genealogy research. But lots of challenges interpreting SNP data in genealogical terms.
Now, if I can just find a way to embed advertisements in SNP data. Ooooh! Better yet, June Carter.
Another unexpected result of gene chips: Identifying hidden incest in the course of routine tests for developmental disabilities:
Houston doctors are reporting that the newest generation of DNA testing, now in wide use, is revealing many previously missed incest cases that raise difficult legal and ethical questions.
Children born to first-degree relatives have a developmental disability about half the time, said Beaudet.
Baylor began using the new test about six months ago. During that time, Beaudet said, the lab has seen evidence of incest fewer than 10 times.
"Half the time" seems high to me, but would explain the high positive rate here.
(via Razib)
Misha Angrist has written a strong guest post at Daniel MacArthur's "Genetic Future", taking a clear stand in favor of disclosure of genetic information from research studies. In response to the argument that full access to genetic information might "disturb" people:
If you told me I had an inoperable tumor, don’t you think that would mess with my head? In the old days, doctors wouldn’t tell their patients such things (I know, I know—you’re not my doctor). But anyway, who the hell are you to decide what might or might not mess with my head? How do you know I won’t be more upset if you DON’T tell me? And why would it jeopardize my ability to get insurance? Because I’m only asking you to disclose it to ME, not to append it to my medical record or my Facebook page. Your consent form says you will take all kinds of steps to keep my information confidential, but that it might be examined by the FDA, the NIH, etc. So…that means it would be okay for some bureaucrat to peruse it but not me?
Well, of course. Bureaucrats mind your own business so you don't have to!
A new paper in PNAS by Erik Trinkaus covers the mortality patterns of old versus young adults in Neandertals, early modern humans in the Levant and early Upper Paleolithic people of Europe [1]. The paper has gotten a lot of attention from the press, including the NY Times: "Life Span of Early Man Same as Neanderthals’". Reporters worldwide (so far, 30 articles in Google News) were relying on a press release issued from Trinkaus' university.
I read this paper and got a sinking feeling. The results and methods looked to me very similar to those used by Rachel Caspari and Sang-Hee Lee in a series of papers from 2004 onward [2] [3] [4] [5]. Their initial paper attracted comments by Kristen Hawkes and James O'Connell [6], and Tom Minichillo [7]. This has been an active and highly cited research pathway with papers in PNAS, the American Journal of Physical Anthropology and the Journal of Human Evolution. I was extremely surprised that Trinkaus hadn't cited any of this work.
Anyone can compare these papers and draw their own conclusions. In my opinion, the results reported in the press are not new.
Caspari and Lee compared the proportions of old and young adults in Neandertals, early Upper Paleolithic and (in their 2006 paper) early modern humans. They ignored juvenile remains and focused only on the subject of adult mortality, only in those two age classes. They assigned the dental remains to categories based on wear criteria and tested the significance of sample differences. They showed that early modern humans and Neandertals have similar ratios of old to young skeletal remains. They tested whether burial versus non-burial archaeological contexts might influence the observed ratio of older to younger individuals. They demonstrated limits on the phylogenetic interpretation of the results and suggested behavioral and cultural factors that could account for them. I think their work was clever and simple, but more important it has been highly cited and presented at national meetings. These are not obscure sources.
I'm not the citation police -- I probably make more errors than anybody. But in my opinion Trinkaus' new paper uses substantially the same methods and finds the same results as Caspari and Lee without giving them credit. I find only one difference in method -- Trinkaus cut off his age categories at 20 and 40 years instead of 15 and 30. And one difference in result -- Trinkaus found fewer older adults in the early Upper Paleolithic compared to Caspari and Lee. If either difference is important, there's no citation to let us know why. It's like Caspari and Lee's papers have slipped down the memory hole.
NAS members can submit papers to PNAS directly, relying on reviews from peers that they select themselves. The editorial policy of the journal makes it very difficult to reply to these papers, and certainly no reply could gain the attention that this paper has already received.
Lucky for me, I just happen to have a blog for such occasions.
I wrote to Trinkaus to invite him to provide his comments for me to publish them along with my post. I knew he would probably have a different interpretation than me of the issues. He very kindly took the time to compose replies to my questions. I publish them here unedited along with my follow-up questions.
His comment on my initial request:
Thanks for this. I intentionally did not refer to those papers since they, at least in the original PNAS paper, completely ignored taphonomical and behavioral issues. My original 1995 paper, which I seem to remember they did not cite (I am in Spain on a slow internet connection), heavily emphasized those issues, and this paper does as well. The issue is not just longevity - it is its combination with all of the various biases in the samples, biases which are just as important as the presumed demographic ones.
Best, Erik
My first followup:
Thanks, Erik, I really appreciate your reply. I hope Spain is treating you better than Wisconsin is treating me this week!
Naturally I disagree but I am very glad to be able to include your comment.
I did check the citations of all the papers, thinking that you might have missed them for that reason. They did cite you. The 2004 PNAS paper discusses taphonomy extensively, including the quantitative comparison of burials versus non-burials. The exchange with Hawkes and O'Connell also discusses taphonomic issues. The behavioral issues are the subject of the 2006 paper, which was titled "Is human longevity the consequence of cultural change or modern biology?"
--John
Trinkaus' reply:
Two comments.
I do not make it a point to quote everybody with whom I might disagree.
Your blog on the Zhirendong mandible could have benefitted from a reading of Weidenreich, Dobson and Trinkaus and/or Schwartz and Tattersall on what constitutes a modern human chin. Saint Cesaire and the Vindija mandibles do not have it, any more than ER 730 does, despite incipient trigones on them.
I wrote back:
Hi, Erik --
Thank you again for your responses. They have helped me to understand your position.
If PNAS has the same review standards as my blog, maybe I should just concede. It would take fifty undergraduates to find all my errors.
But I think we completely agree that a scholarly mandibular description should cite the sources you mention, both classic and recent.
What I don't understand is why you disagree in the present case. If you had ignored Rachel and Sang-Hee's papers because you thought they had nothing of value, why did you use such similar methods and come to such similar conclusions? Did you think those methods and conclusions were so obvious that they don't need citation? If so, then why did you issue a press release?
--John
Trinkaus replied:
I originally found the Caspari and Lee PNAS paper unconvincing, and put it out of my mind. None of my peer-reviewers noted its absence, and it was not cited in recent papers relating to the topic (i.e., Smith et al. 2010). It did not occur to me to cite it, and nor did it occur to other people directly and actively involved in Neandertal/modern human life history. Hence it was not there.
I did not previously comment on the your blog on the Zhirendong mandible, since I almost never respond to such commentaries. I only did it since you raised issues relating to your blog. That paper appears to have set a record for misquotes (Dennell could not possibly have read it for his Nature commentary).
Best, Erik
I finished the exchange:
Hi, Erik --
Well, thank you again for taking the time to comment. I do appreciate it, particularly since you're out of the country.
--John
I think our exchange was much more productive than a formal comment could be. Trinkaus wrote that his omission had been intentional, and I take him at his word that he "put it out of his mind". I am glad that I was able to bring his attention to the problem, though I surely wish that a better review had been done in the first place. I'm sure he still disagrees but I hope he will take the opportunity to engage with the current literature. Maybe someone can suggest some more studies to replicate.
I've pretty consistently criticized scientists who issue hyped-up press releases. They draw my attention. It is a frequent feature of press releases that they claim unmerited novelty and ignore prior work. This feature rarely creeps into the actual published paper in such an obvious way.
I'm also disturbed by the power imbalance this case demonstrates. Sitting here watching MythBusters with my daughter who wants to be a scientist someday, I hope we can start to do better.
Ronald Bailey writes in the January Reason about his experiences with personal genomics ("I’ll Show You My Genome. Will You Show Me Yours?"). He's a booster, and much of the article is a review of basic objections (privacy concerns, weakness of gene-phenotype associations, imprecision) and some replies to them. He has several passages worth quoting, including this one:
Some time before the end of this decade, kids are going to be running gene scans and maybe even whole genome sequencing experiments in their ninth-grade biology classes, just the way some of us did blood typing experiments back in the mid-20th century. Then they are going to share that information with their friends on whatever social media follow Facebook and Twitter, and they’ll do it without parental consent. Nerdy high school sweethearts might swap DNA profiles and run them through computer programs designed to predict what their potential children might look like. In the process, of course, they will also be sharing information about their parents’ genes.
We're just starting a new decade, I had to remind myself. Gene chips probably will be cheap enough then to run in high school labs. Is there anyone who's thinking about the need to teach high school kids about factor analysis? Bayesian inference? Because I find a twisted appeal in the idea that postdocs now are doing what high school science projects will be about in ten years.
I've thought for a long time that most of the basic analysis of genomes is undergraduate-level work. Most of the effort is learning how to use software, which is not mathematically demanding but does take time.
Writing the software is a different issue. But as we apply the same techniques to more and more organisms, there will be no new software to write for most analyses. Plug in your data, assuming that you've been sensible enough to define an appropriate sampling strategy, and the software will give you an answer.
Consider a time when genotyping can be done for $2 a chip in bulk. Each year, a new chip design is distributed to high schools across a state. One year, it may be dandelions. The kids sample yards across the state, collect plant phenotype data, and submit data to a common pool. Dispersal patterns, flowering time, other phenotypes are all possible targets of study. A structured population enables them to stratify their sample, exploit linkage due to historical events, and study traits linked to biological invasion.
For the price of one R01 grant, kids across a whole state might develop a new model organism, learn the principles of genomics and produce the data equivalent of dozens of research papers.
UPDATE (2010-12-15): A reader writes quizzically:
I can't figure out what you are saying here. That it's all so simple that high school kids will understand it without any training in statistics? That all possible analyses of genomic data have already been devised, and all that's left is to turn the crank? Maybe I'm just dense, but I think you need to describe the twisted appeal you're experiencing, not just report it.
What good will the data be from gillions of dandelion gene chips, if the kids don't have the time to measure umpteen different dandelion phenotypes to correlate with the gene data? Whose judgment will decide which traits to consider, and will high school teachers have that judgment? Etc.
Are you saying the software already exists to correlate (or fail to do so) the mountains of new human gene chip data with all of the subjects' medical and life history data? Or are you saying that this is exactly the problem?
I'm honestly not sure if you are in frank trans-humanist pro-technocracy mode, or if you are ironically alluding to its liabilities.
Never assume a blog post has a well-formed point.
I think the potential study I describe is one with enormously more power than anything being done today on plant dispersal, and with power at least equal to the best work on gene-phenotype associations in model organisms (setting aside developmental biology).
Kids in school aren't statisticians, but thousands of them do have brute force on their side. I don't see any obvious reason why software can't be written to spit out these answers. Naturally that software will have to make lots of assumptions, which means that somebody is going to have to design a sensible sampling scheme that can be carried out by students, allowing for their lack of training. It's an educational challenge, but I'd say it's' doable.
This means, of course, in 10 years the statistics that support this kind of study won't be interesting to the kinds of people who write such software. The science progresses. I hope that in 10 years the real scientists will be doing something a little better than what the software will be able to spit out.
At the same time, I think we have to acknowledge that most of what today's genomics postdocs are doing is exactly the kind of analysis that I'm describing for high school kids in 2020, except with much smaller, poorly-designed samples. What makes this Ph.D.-level work is that our current software is not very good at it -- in large part because the current software is mostly written by postdocs with little training in systems design.
Via a reader: The Daily Mail really aims for the lowest common denominator of genetics: "We've all suspected, now it's official: Ozzy Osbourne IS a Neanderthal"
He claims his ‘superhuman’ genes have kept him healthy despite a lifetime of rock ’n’ roll excess.
And now it seems science may back up Ozzy Osbourne’s theory that he has a particularly hardy family tree.
Researchers studying his DNA have found that the singer is the descendant of a Neanderthal man.
This is almost an entry in the Neandertal anti-defamation series. What holds it back is the clear involvement of some shady genetics company. Get this:
The researchers also examined the gene the body uses to break down alcohol and discovered an ‘unusual variant’ which could have helped Osbourne survive during the years when he drank up to four bottles of Cognac a day.
‘Given the swimming pools of booze I’d guzzled over the years – not to mention all the [drugs] – there’s really no plausible medical reason why I should be alive,’ he told The Sunday Times.
What a crock! I mean it's one thing to tell people their genomes have Neandertal markers. I mean, that's a crock, too, since we have no clear marker list yet. But at least it's a harmless entertainment-only kind of a crock.
Now, when you tell an alcoholic that he has an "unusual variant" that "could have helped" metabolize alcohol better -- that's an altogether deeper level of crockery.
I know, it's like the "Weekly World News", but cheez Louise, what a crock!
One of the incredible benefits of the open source approach to genomics is that non-practitioners have a chance to see how interpretations are built. Sometimes it's a real "warts and all" picture of science, as statistical and historical details come into conflict with each other.
The group at Genomes Unzipped includes a group of forward-thinking geneticists and related professionals who have made their 23andMe genotype data public. Soon after their data release, some other folks went to work on the data. Dienekes Pontikos applied ancestry prediction algorithm, finding that the Genomes Unzipped authors were, no surprise, mostly European -- but two of them were predicted to have a high component of Ashkenazi Jewish ancestry.
Genomes Unzipped participant Joe Pickrell was surprised to discover he might have a high fraction of ancestry tracing back to Ashkenazi Jews. So he did some investigation of his own:
Several hours after we released our data, however, I was pointed to a post where Dienekes Pontikos wrote about the results of running all our data through his ancestry prediction program. While just about everyone was quite confidently predicted to be almost entirely of northwestern European descent, this analysis gave me a point estimate of 20% Ashkenazi Jewish ancestry. Within hours, several people had asked me about this, and I had no real response. So I decided to take a look at the data myself; some basic analyses are below.
The post is a great summary of some basic methods, including the strengths and weaknesses of the assumptions that underlie them.
I have found over the last several years that this "surprised to discover" reaction is very common among people who have ancestry testing or other genotyping done. Sometimes the surprises end up being well supported by other historical evidence, of which the subject may not have been aware. But more often, the "surprising genealogy" is just an artificial result of applying erroneous or simplified assumptions in the course of the analysis. I think it is tremendously important to write up case studies where the process leading to a result is explicated, where the sensitivity of the analysis to various assumptions can be probed.
The Guardian is running an essay by two British GP's about the consequences of cousin marriage in the UK: "Cousin marriages: a question of understanding".
The fact remains that this is a health issue, which has lead to a higher than normal infant and perinatal mortality in cities such as Birmingham and Bradford. The extent of the morbidity is not yet known, but a fair indication can be found in the rise in the number of applications for disability living allowances for children in these areas. A disproportionate number of cases occur among those of south Asian, and especially Pakistani descent, but it can affect all ethnicities and should be a concern for all. It is time to discuss it rationally so we can enable informed reproductive choices.
The topic of cousin marriage highlights the cultural tensions with immigrant populations in Europe, the demographic impacts of immigration (where the pool of culturally preferred partners is not as large as in the nation of origin), and the economics of integrating high-fertility immigrant populations into national health programs. From the evolutionary perspective, it highlights the importance of founder effects and demography in determining disease risk.
It strikes me as a case where genetic testing might provide positive benefits in human and economic terms, yet not without cost to cultural preferences and government ambitions. Legal prohibitions on cousin marriage reflected first and foremost dynastic concerns (limiting the concentration of power in aristocratic families), but later mostly eugenic concerns. The mating behavior of aristocrats is no longer a serious issue for most of us. If genetic testing can substantially reduce the risk of autosomal recessive disorders for the offspring of cousins, doesn't that negate the eugenic argument?
The authors mention genetic testing only briefly, mentioning that it cannot eliminate all risk of all rare autosomal recessive disorders because we cannot test for every possible disease-associated variant. That is true, but at some point the effectiveness of screening for known variants makes the additional risk of cousin marriage very slight compared to the ordinary risk in outbred marriages.
What remains is the question of inbreeding depression. How important are genes of small effect to phenotypes we care about? If they're very important, then health-related phenotypes may be suboptimal in offspring of cousin marriages even if no Mendelian disorder is present. This would be a broad eugenic argument for banning cousin marriage, even with the availability of testing.
How far can this eugenic argument go? Maybe public health advocates should cast their net more widely, encouraging outbreeding on a broader scale than immigrant communities. You see how these topics are intertwined -- eugenics, genetic testing, and State regulation of marriage. The GP authors of the Guardian piece make all the standard points, which amount to "Won't anyone think of the children!?" But where does this turn into explicitly eugenic arguments, such as Oliver Wendell Holmes' famous, "Three generations of imbeciles are enough"?
I'm inclined toward the opinion that people should choose themselves, and technology should facilitate their choices, not foreclose them. The State may educate, it shouldn't dictate. But not everyone agrees, and most argue for some point at which the State should bar people from destructive choices. But where is that, and who should control the information? That's what's at stake in genetic testing.
In your blog, you have commented on the prospect of re-creating
a neandertal from a "completed" genome.....I agree with your views
and predictions.However, given the apparent widespread occurrence of small pieces
of the neandertal genome in contemporary humans, there should be
a large variability in the fraction of each person's genome which he/she
shares with at least the small number of neandertals whose DNA has
been sampled.And though one could argue that ethics would be trampled, one could
selectively breed exisiting humans to enhance their complement of
neandertal genes. Not that I am suggesting this should be done, but
such breeding could be entirely voluntary, may have already occurred,
and would overcome at least some "Jurassic Park" and Frankensteinian
objections to the enterprise??
You bet -- that's not only plausible in principle, it's exactly what people are trying to do with cattle to backbreed something like aurochsen.
The success (not withstanding the time required) hangs on the distribution of Neandertal variation in the current genome. We don't know yet how clustered it is -- is it a 3 percent average, but people have random parts, or is it that most people share the same 3 percent? If it's more scattered, then a larger representation of the Neandertal genome still exists, distributed among many people; if not, we may not be able to get more than a few percent of a Neandertal by backbreeding.
