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November 12, 2013

Vaccination, and social information networks

Filed under: Medicine,public health,Vaccination — Razib Khan @ 1:34 am

Preventable

If you have not read Julia Ioffe’s story about getting whooping cough at the age of 31 (also see follow up), you might want to. Here’s some further context, Vaccine Refusals Fueled California’s Whooping Cough Epidemic. This topic has been covered and dissected in great detail by many writers and scientists, so I won’t repeat what you already know in regards to herd immunity. There’s no point in preaching to the choir.


Rather, I want to offer a personal perspective. Over the past few years I’ve become much more aware of cultural streams in public health, and the public’s reaction to that health advice, because I have become a father. More specifically, when my wife was pregnant with my daughter, and after she was born, we encountered major pressure from peer networks to not vaccinate. In the social circles in which we were embedded, “progressive,” “crunchy,” and “alternative,” vaccinating one’s child was the heterodox decision. It was rather obvious to us that one of the major reasons that many people do not vaccinate their children is that many of their friends, and vocal people whom they trust, do not vaccinate their children. We were able to resist and rebuff any peer pressure rather easily because we have a much stronger scientific background than most Americans, but it isn’t hard to imagine being ignorant and trusting those in whom you normally put your trust.

In some ways I am not totally unsympathetic to the skepticism that some in the public have toward the medical establishment. Modern scientific medicine is a genuine miracle, but most of its gains arguably occurred in the first half of the 20th century through public health campaigns, vaccination and antiobiotics. Though the decline in heart disease is a major result which we should celebrate, it is arguably less significant than the sharp reduction in deaths of the young due to numerous infections (heart disease tends to effect the old). Additionally, diseases such as cancer are subject to the problem of what Jim Manzi terms “high causal density”. Cancers, like many diseases of late life, can have many triggers and factors impacting their likelihood, so solving the problem at the root may not be so simple. In reaction to this complexity and uncertainty I do believe that on occasion the medical profession and the public health establishment have unduly emphasized their certainty.

Like the reality that the variegated public health concerns we have today, such as type 2 diabetes and cancer, are probably better problems than endemic smallpox, tuberculosis, or scarlet fever, the downsides of having a medical establishment which on occasion oversteps the bounds of its reasonable confidence are overridden by the upsides. We have empirical evidence of this, because there are nations without medical establishments, and they are not flourishing. But that does not change the reality that a population shielded from the brutal knife of infectious disease and plague is somewhat befuddled by the mysteries of the slow and subtle ailments which are the afflictions of modernity.

One response is the liberal individualist one. Though we may bemoan Steve Jobs’ experimentation with alternative therapies for his cancer, it was his individual choice. It gets more complicated what you have children, who are under the control of their parents. Again, I’m not going to go over the controversies over groups like Christian Scientists, whose children have died due to withholding medical treatment. The cultural consensus seems to be that parents have a right to impose all sorts of crazy beliefs and practices upon their children, but not those which may result in death. Then you move to the issue that when it comes to vaccination one can’t seal off individual choice from consequences to the public. It seems entirely likely that for the next decade we may be seeing a conflagration of preventable diseases among certain segments of the American demographic, and those who they live among, because of cultural fashion. The collective choices of parents opting out from vaccination is subject to negative feedback dynamics. Early dissenters can “free-ride” on herd immunity, and indulge their quackery, but beyond a particular threshold disease and death will come back to the fore. But human beliefs are often rather well insulated against falsification for a great deal of time. The AIDS denialst community is a testament to this phenomenon; it persists despite mysteriously (to them) high mortality rates among its most vocal proponents.

So is there a solution? Conscience is a value which Americans pride, even unto death. I do not see the powers that be intervening in these cases. Rather, this groundswell of denialism must be countered by public opprobrium, and yes, shaming. Peer pressure kills, but it can also save lives. As a matter of safety people with small children should investigate rates of vaccination in their community (young infants are not vaccinated, and so are particularly vulnerable to infections which are dampened by herd immunity). They should move when a dangerous critical mass is present. If people ask, those who leave should explain their rationale. Actions can speak louder than words. Where Authorité falls on deaf ears, the judgment of the populace might be heeded.

The post Vaccination, and social information networks appeared first on Gene Expression.

October 29, 2012

Doctors are apparently gods, get used to it

Filed under: Genetics,Genomics,Medicine — Razib Khan @ 8:24 am

Here’s a caption from a Time article, What Your Doctor Isn’t Telling You About Your DNA:

Nice to know that two physicians in Philadelphia not only have medical degrees, but specialize in mind-reading the parents of this nation! Above the caption is a photo of  the two concerned and worried looking professionals in question. Let me quote the first two paragraphs of the article:

The test results were crystal clear, and still the doctors didn’t know what to do. A sick baby whose genome was analyzed at the Children’s Hospital of Philadelphia turned out to possess a genetic mutation that indicated dementia would likely take root around age 40. But that lab result was completely unrelated to the reason the baby’s DNA was being tested, leaving the doctors to debate: Should they share the bad news?

When it comes to scanning DNA or sequencing the genome — reading the entire genetic code — what to do with unanticipated results is one of the thorniest issues confronting the medical community. Many conflicted discussions followed the dementia discovery at the Children’s Hospital of Philadelphia (CHOP) before a decision was reached: the parents would not ...

April 16, 2012

None dare call it eugenics!

Filed under: Genetics,Human Genetics,Medicine — Razib Khan @ 8:37 pm

Well, almost no one:

“The unspoken central reason for the societal taboo and the penal ban on incest is the possibility of hereditary defects — a factor that Strasbourg only hinted at. But the intention behind the eugenic argument is one that is indefensible, and not just in Germany with its terrible Nazi past: The increased risk of hereditary defects does not justify a legal ban. Otherwise you would have to legally ban other risk groups, like women over 40 or people with genetic diseases, from having children. Does anyone truly want to prevent predictable disabilities using penal measures and thus deny disabled children the right to life in 2012? That’s absurd. And yet such fears of genetic damage are precisely what shape the punishibility of sexual intercourse between siblings.”


There are a set of arguments against near relation incest which strike me as generally ad hoc. And there’s social science to back that up. Incest is reflexively disgusting to most people (depending on how it is categorized). But disgust alone is not a sufficient grounds for banning a practice in educated circles today, so people create rationales after the fact. ...

April 8, 2012

Doctors and life expectacy

Filed under: Medicine — Razib Khan @ 4:18 pm

A friend pointed me to the following infographic on the concentration of doctors per county. The orange represents “very high need,” and dark blue “very low need.”

Now let’s compare it to life expectancy by county:

February 13, 2012

American medicine & American red-tape

Filed under: Health,Human Genetics,Human Genomics,Medicine — Razib Khan @ 6:08 pm

I just attended a presentation where a researcher outlined how epigenomics could help patients with various grave illnesses. Normally I don’t focus on human medical genetics too much because it always depresses me. I don’t understand how medical geneticists don’t start wondering what hidden disease everyone around them has. In any case the researcher outlined how epigenomic information allowed for better treatment, so as to extend the lives of patients. All well and good. But then one individual in the audience began asking pointed questions as to the medical ethics of the enterprise, and whether the researcher had cleared some legally sanctioned hurdles. More specifically, there was a question whether exploring someone’s epigenomic profile might expose private information of their relatives! (because relatives share epigenomic and genomic profiles to some extent)

Frankly I began to get enraged at this point. People are suffering from terminal illnesses, and considerations of the genetic privacy of their near relatives are looming large? Seriously? The reality is that manifestation of a disease itself gives one information about the risks of their relatives. In any case, the researcher admitted that further progress in this area is probably going to be due to the investments of wealthy individuals (e.g., people like Steve Jobs who have illnesses) as well as outside of the United States. You’re #1 America!

January 1, 2012

“Doctors don’t cure nothing”

Filed under: Causation,Correlation,Culture,False Positives,Medicine,science — Razib Khan @ 2:00 pm

NSFW


As I observed before, modern medicine is subject to some of the same statistical issues as social science in its tendency to put unwarranted spotlight on preferred false positive results. Trials and Errors – Why Science Is Failing Us:

This doesn’t mean that nothing can be known or that every causal story is equally problematic. Some explanations clearly work better than others, which is why, thanks largely to improvements in public health, the average lifespan in the developed world continues to increase. (According to the Centers for Disease Control and Prevention, things like clean water and improved sanitation—and not necessarily advances in medical technology—accounted for at least 25 of the more than 30 years added to the lifespan of Americans during the 20th century.) Although our reliance on statistical correlations has strict constraints—which limit modern research—those correlations have still managed to identify many essential risk factors, such as smoking and bad diets.


I need to look at the difference between mortality and morbidity here. The two are clearly related, but if modern medicine has decreased morbidity, then it is still worthwhile to a greater extent than simple life expectancy calculations might indicate. But the reality is that the more and more I look at modern medicine the more worried I get that the age old heuristics and biases which allowed medicine to flourish as a form of counterproductive psychotherapy up until the early 20th century are now coming back to the fore. The issue here is less the profession of medicine, as the incentives and impulses which drive the need for a “cure” from the demand side.

All this brings to mind a passage from the book Religion Explained:

E. E. Evans-Pritchard is famous for his classic account of the religious notions and beliefs of the Zande people of Sudan…one day the roof of a mud house collapses in the village…People promptly explain the incident in terms of witchardcraft…Evans-Pritchard points out to this interlocutors that termintes had undermined the mud house and there was nothing particularly mysterious in its collapse. But people are not interested in this aspect of the situation. As they point out…they know perfectly that termites gnaw at the pillars of mud houses and that decrepit structures are bound to cave in at some point. What they want to find out is why the roof collapsed at the precise time when so-and-so was sitting undernearth it rather than before or after that. This is where witchcraft provides a good explanation.

With all due respect to modern scientifically trained physicians, but the demands that their patients are now making upon them in terms of curing diseases whose causal roots are less than clear are transforming them into latter-day shamans. As it was, it will be?

December 30, 2011

Eggs: quantity and quality

Filed under: Fertility,Medicine — Razib Khan @ 3:05 am

In my post below on selection for the “better” zygote Michelle observes that “This would be relatively easy for the father, not so much for the mother.” I took her to mean either of two things,

1) Extraction of eggs is a major surgical affair. Extraction of sperm is not.

2) Males generally have many more sperm to contribute than females.

The latter issue made me go look for data on human females, by age. The paper A systematic review of tests predicting ovarian reserve and IVF outcome had what I was looking for. First, let’s review the cumulative distribution of fertility curves for women:


The way I read the figure 50% of women are sterile at 41. 50% begin their fertility drop at 31. Note that a small, but significant, minority of women are already sterile by age 35. People talk about fertility curves, but less weight is given to the fact that the curve varies in terms of its chronology!

Second, let’s look at the number and quality of ovarian follicles over time (they correspond to number of incipient eggs):

This figure is not easy to read. But you can see that at age 20 there are ~100,000 follicles. That number seems to drop by a little less than half by 30, and is at 20,000 by 40. But by this point 25 percent are of “poor quality.”

December 17, 2011

Promiscuity and vaginal bacterial diversity

It’s a fun fact that there are an order of magnitude more bacterial cells in your body than your own cells. Not only that, it’s well known that we wouldn’t flourish, let alone survive, without our gut “flora,” which digest material which would otherwise pass through out system. Not only are microbes good for us, but they’re also bad for us. The evolutionary flexibility of microbial pathogens is one of the major arguments for why sex exists among multiceullar species: it allows them to adapt to rapidly fluctuating disease pressures. Therefore, obviously the ecology of multicellular organisms’ microbial flora is essential to properly characterize. One element of the project involves genomics. This is not so easy for microbes because we don’t have the reference sequences of most of these organisms. We rely mostly on species which are easy to culture, and that does not include most lineages in the wild. That being said, there are workarounds, such as looking at the 16S rNA sequence, which is strongly constrained in bacterial lineages (i.e., it can serve as a “clock” to measure divergence of very deeply separated lineages).

With that, a new paper, Promiscuity in mice is associated with increased vaginal bacterial diversity:

Differences in the number of sexual partners (i.e., mating system) have the potential to exert a strong influence on the bacterial communities present in reproductive structures like the vagina. Because this structure serves as a conduit for gametes, bacteria present there may have a pronounced, direct effect on host reproductive success. As a first step towards the identification of the relationship between sexual behavior and potentially pathogenic bacterial communities inhabiting vital reproductive structures, as well as their potential effects on fitness, I sought to quantify differences in bacterial diversity in a promiscuous and monogamous mammal species. To accomplish this, I used two sympatric species ofPeromyscus rodents—Peromyscus californicus and Peromyscus maniculatus that differ with regard to the number of sexual partners per individual to test the hypothesis that bacterial diversity should be greater in the promiscuous P. maniculatus relative to the monogamous P. californicus. As predicted, phylogenetically controlled and operational taxonomic unit-based indices of bacterial diversity indicated that diversity is greater in the promiscuous species. These results provide important new insights into the effects of mating system on bacterial diversity in free-living vertebrates, and may suggest a potential cost of promiscuity.

These two species are sympatric and exhibit very different behaviors. Sympatric means that they aren’t geographically separated, so they are subject to the same environmental conditions. Rather, their distinctions on the species level seem to be due to behavior, in this case, the number of sexual partners of females. This then is a nice test for assessing the relationship of microbial diversity in the vagina as a function of partners. I suspect a priori you’d expect a positive relationship. And that’s what the author found. He presented a diversity index, but the results are rather intelligible visually. You can see clearly that the promiscuous species is characterized by a greater range of species richness than the monogamous one.

There are some studies of metagenomics of bacterial communities in humans. But to my knowledge it doesn’t look like there are any which have attempted to correlate number of sexual partners to diversity of vaginal flora. This is possible very important as a long term issue. The evolutionary biologist Paul Ewald has been reporting that there is a connection between history of infection and many late in life diseases, such as cancers. Mike Snyder had Stanford has been tracking his own biomarkers in extensive detail for several years, and has indicated that his own onset of Type II Diabetes was probably triggered by an earlier infection. These inferences were only possible because of his extremely rich personal data set, part of a broader project in his laboratory. But, it might give us a window into the more precise individual etiologies of diseases.

Citation: Naturwissenschaften. 2011 Nov;98(11):951-60. Epub 2011 Oct 1

Image Credit: Wikipedia, Wikipedia.

October 1, 2011

Up with nurses! Down with doctorates!

Filed under: Medicine — Razib Khan @ 12:48 pm

In light of growing health care costs and the demographic reality of an aging profession stories like this one in The New York Times are both depressing and hopeful. Calling the Nurse ‘Doctor,’ a Title Physicians Oppose:

But while all physician organizations support the idea of teamwork, not all physicians are willing to surrender the traditional understanding that they should be the ones to lead the team. Their training is so extensive, physicians argue, that they alone should diagnose illnesses. Nurses respond that they are perfectly capable of recognizing a vast majority of patient problems, and they have the studies to prove it. The battle over the title “doctor” is in many ways a proxy for this larger struggle.

Six to eight years of collegiate and graduate education generally earn pharmacists, physical therapists and nurses the right to call themselves “doctors,” compared with nearly twice that many years of training for most physicians. For decades, a bachelor’s degree was all that was required to become a pharmacist. That changed in 2004 when a doctorate replaced the bachelor’s degree as the minimum needed to practice. Physical therapists once needed only bachelor’s degrees, too, but the profession will require doctorates of all students by 2015 — the same year that nursing leaders intend to require doctorates of all those becoming nurse practitioners.

Nursing is filled with multiple specialties requiring varying levels of education, from a high school equivalency degree for nursing assistants to a master’s degree for nurse practitioners. Those wishing to become nurse anesthetists will soon be required to earn doctorates, but otherwise there are presently no practical or clinical differences between nurses who earn master’s degrees and those who get doctorates.


I applaud the wider distribution of medical services outside of the licensing monopoly of M.D.s. As an empirical matter I think there was a practical reason for the professionalization of medicine in the 20th century and the emergence of degree holding as necessary. To be frank about it for most of human history doctors were frauds or butchers. Modern medicine in the 20th century was a major revolution in that sense (though doctors are only part of it, the rise of an effective pharmaceutical industry is probably just as important if not more so). But the arrow of history does not always move in one direction, and we live in an “information age.” Doctors are human, and therefore fallible. They need the aid of both their patients and various other medical professionals to optimize health outcomes. The paternalistic model is just not viable in the long run, especially as the median educational qualifications of their patients keeps rising.

But notice that in this case we’re seeing greater and greater credentialism in fields which were traditionally perceived to be auxiliary to medical doctors. This is not a good sign. Instead of challenging the unquestioned prominence of medical doctors in domains where nurses are sufficient and more cost effective, the nursing profession is “fighting fire with fire.” This is not going to end well. Having to pile on education removes productive years in the work force. This is justifiable when education results in gains in productivity, but just as in education, I suspect that all the extra years for physical therapists and nurses is not doing anything but signalling, and further tightening up labor supply as the number of patients keeps on increasing because of the aging of the population.

August 15, 2011

Getting better sperm donors

Filed under: Genetics,Medicine,Sperm donors — Razib Khan @ 10:53 pm

The British newspapers have been reporting on a bizarre story about a Dutch sperm donor who hid a history of mental problems from recipients. I didn’t pay much attention to it because of the British tabloid media’s tendency to sensationalize. But Radio Netherlands also reported the outlines of the story, and there seems to be validity to the broad facts at hand. A Dutch man with a history of mental illness did father many children by offering his services online, and hiding various conditions from potential mothers. Now several of the children have developed the same problems (e.g., autism).


But the specific case here highlights some constraints on sperm donation which seem to have resulted in a “gray market” which allowed this man to “slip through” the safeguards. And yet I wonder why there is so much regulation of sperm banks in the first place? It reminds me of a story from a few years back about panic in Turkey over the importation of “foreign sperm.” Is there is a strong public policy reason why we should have a sperm donor shortage? In an ideal world children should know their parents, but there are far greater social ...

August 10, 2011

Crohn’s disease is about barely keeping you alive

The Pith: Natural selection is a quick & dirty operator. When subject to novel environments it can react rapidly, bringing both the good and the bad. The key toward successful adaptation is not perfection, but being better than the alternatives. This may mean that many contemporary diseases are side effects of past evolutionary genetic compromises.

The above is a figure from a recent paper which just came out in Molecular Biology and Evolution, Crohn’s disease and genetic hitchhiking at IBD5. You probably have heard about Crohn’s disease before, there are hundreds of thousands of Americans afflicted with it. It’s an inflammatory bowel ailment, and it can be debilitating even to very young people. The prevalence also varies quite a bit by population. Why? It could be something in the environment (e.g., different diet) or genetic predisposition, or some combination. What the figure above purports to illustrate is the correlation between Crohn’s disease and the expansion of the agricultural lifestyle.

But don’t get overexcited Paleos! There are many moving parts to this story, and I need to back up to the beginning. The tens of thousands of ...

July 25, 2011

Dominance, the social construct that confuses

Filed under: Dominance,Genetics,Health,Medicine,Penetrance,Sickle cell — Razib Khan @ 12:31 pm

A story in The Los Angeles Times seems to point medical implications of being a sickle cell carrier, Sickle cell trait: The silent killer:

At least 17 high school and college athletes’ deaths have been tied to sickle cell trait during the past 11 years. The group includes Olivier Louis, a player at Wekiva High School near Orlando, who died on Sept. 7, 2010, following his first football practice.

You have surely heard about sickle cell anemia. It is a recessive disease which expresses in those who carry two sickle cell alleles. T-boz of TLC has the disease for example due to her homozygosity. But the allele also famously confers some resistance against malaria, which explains its concentration in regions which have historically been malarial. Sickle cell is arguable the classic case of heterozygote advantage driving the emergence of a recessive disease. The frequency of the allele is balanced at the equipoise between the proportion of people who are more susceptible to malaria if its proportion is too low and those who express sickle cell anemia if its proportion is too high. This advantage is obviously context sensitive. The ...

July 20, 2011

Bacteria tell the tale of human intercourse

Filed under: Anthroplogy,Austro-Asiatic,Genetics,H. pylori,Medicine,Southeast Asia — Razib Khan @ 12:39 am

The Pith: the genetic relationships between bacteria in our stomach can tell us a lot about the relationships between various groups of people. Additionally, the distribution of different strains of bacteria may have significant public health implications.

The above image is from a paper which was pushed online yesterday in PLoS ONE: Evolutionary History of Helicobacter pylori Sequences Reflect Past Human Migrations in Southeast Asia. It’s a paper which caught my attention for several reasons. First, I’ve exhibited some curiosity about the history and prehistory of Southeast Asia of late. Elucidating this region’s historical dynamics may bear upon more general questions of human evolutionary and cultural process. Second, H. pylori is a fascinating organism whose connection to specific human populations is tight enough that it can shed light on past interactions of different groups. In short, just like humans H. pylori exhibits regional specificity and local history. But additionally, H. pylori is also subject to natural selection after introduction into a new population, and so can serve as a window upon cultural contacts which might otherwise leave a light demographic footprint. In other words, the spread of ...

June 12, 2011

You are a mutant!

ResearchBlogging.org
The Pith: You are expected to have 30 new mutations which differentiate you from your parents. But, there is wiggle room around this number, and you may have more or less. This number may vary across siblings, and explain differences across siblings. Additionally, previously used estimates of mutation rates which may have been too high by a factor of 2. This may push the “last common ancestor” of many human and human-related lineages back by a factor of 2 in terms of time.

There’s a new letter in Nature Genetics on de novo mutations in humans which is sending the headline writers in the press into a natural frenzy trying to “hook” the results into the X-Men franchise. I implicitly assume most people understand that they all have new genetic mutations specific and identifiable to them. The important issue in relation to “mutants” as commonly understood is that they have salient identifiable phenotypes, not that they have subtle genetic variants which are invisible to us. Another implicit aspect is that phenotypes are an accurate signal or representation of high underlying mutational load. In other words, if you can see that someone is weird in ...

April 13, 2011

When the doctor is a patient….

Filed under: Health,Medicine — Razib Khan @ 11:17 pm

So I’ve been seeing headlines like this today: Physicians Recommend Different Treatments for Patients Than They Choose for Themselves, Study Finds. Here are the numbers:

A total of 242 physicians returned the colon cancer questionnaire (response rate of 48.4 percent), and when asked to imagine they had received the cancer diagnosis, 37.8 percent of physicians chose the surgical procedure with a higher rate of death, but a lower rate of adverse effects. Conversely, when asked to make a recommendation for a patient, only 24.5 percent of physicians chose this option.

The second scenario asked 1,600 physicians to imagine that a new strain of avian influenza had just arrived in the U.S. One group of physicians were asked to imagine they had been infected, and the other group was asked to imagine that his or her patient was infected. One treatment was available for this strain of influenza: an immunoglobulin treatment, without which persons who contract flu have a 10 percent death rate and a 30 percent hospitalization rate with an average stay of one week. The treatment would reduce the rate of adverse events by half, however it also causes death in 1 percent of patients and permanent neurological paralysis in ...

April 4, 2011

Fair & balanced on circumsion

Filed under: Circumcision,Health,Medicine — Razib Khan @ 10:48 am

When Michelle mentioned on Twitter that she was going to write about circumcision, I told her to expect some angry people to come out of the wood-work. Today she has a post up at Scientific American, What’s the deal with male circumcision and female cervical cancer? She concludes:

In addition, while it is true that women with circumcised partners are less likely to get cervical cancer, they are not immune. Women with circumcised partners still contract HPV and develop cervical cancer! They just do it at a reduced rate.

There are other methods that are much more likely to reduce a woman’s chance of contracting HPV and developing cervical cancer, such as vaccination and condom use. Therefore, from a public health standpoint in the United States, it may not be necessary to circumcise male babies solely for the purpose of reducing the risk of cervical cancer in his future sexual partners (of course, this doesn’t take into account the possibility that the child might not be heterosexual).

On the whole I think that Michelle’s take is reasonable and fair-minded. But, I think numbers are of the essence here. What is the expected reduction in rate of risk? This ...

February 14, 2011

Who are those Houston Gujus?

The figure to the left is a three dimensional representation of principal components 1, 2, and 3, generated from a sample of Gujaratis from Houston, and Chinese from Denver. When these two populations are pooled together the Chinese form a very homogeneous cluster. They don’t vary much across the three top explanatory dimensions of genetic variance. In contrast, the Gujaratis do vary. This is not surprising. In the supplements of Reconstructing Indian population history it was notable that the Gujaratis did tend to shake out into two distinct clusters in the PCAs. This is a finding you see over and over when you manipulate the HapMap Gujarati data set. In reality, there aren’t two equivalent clusters. Rather, there’s one “tight” cluster, which I will label “Gujarati_B” from now on in my data set, and another cluster, “Gujarati_A,” which really just consists of all the individuals who are outside of Gujarati_B cluster. Even when compared to other South Asian populations these two distinct categories persist in the HapMap Gujaratis.

Zack has already identified a major difference between the two clusters: Gujarat_A has some individuals with much more “West Eurasian” ancestry. ...

February 3, 2011

Does your twin have “rights” on your genomes?

Randall Parker asks, Genetic Privacy And Identical Twins:

Suppose you have a right to genetic privacy. You might believe you do. Suppose you have an identical twin. Suppose the identical twin decides to publish his (or her) genetic sequence on the web. Do you have the right to stop this?

People who have identical genetic sequences each can get themselves sequenced and then release their genetic data for all the world to download and study. But when an identical twin does this another person also gets their genetic sequence released to the world.

So should twins be able to legally stop each other from publishing their shared DNA sequence on the web?

This is not a question that just applies to twins. As I noted earlier individuals share ~50% of their distinctive genetic material with their parents and full-siblings. I share ~12.5% with first cousins whom I have never met. If I just released my raw sequence by uploading it somewhere I would implicitly “expose” to a non-trivial degree dozens of people (many without their knowledge).


Of course all these issues were considered by the Genomes Unzipped gang. I think they’re right to judge the risks relatively low. Additionally, there’s nothing ...

December 7, 2010

One diabetes gene to explain it all?

372px-PresidentTaftTelephoneCrop
President William Howard Taft

It is the best of times, it is the worse of times. On the one hand the medical consequences of human genomics have been underwhelming. This is important because this is the ultimate reason that much of the basic research is funded. And yet we’ve learned so much. The genetic architecture of skin color has been elucidated, and we’ve seen a clarification of patterns of natural selection in the human genome. The finding last spring of Neandertal admixture in modern human populations is perhaps the most awesome pure science finding of late, coming close to resolving a decades old debate in anthropology. This doesn’t cure cancer, but it does connect the dots about the human past, and that’s not trivial. We are species haunted by our memories, so we might as well get them right!

But all hope is not lost. Research continues. And one area which general surveys of genomic variation have usually shown to be targets of natural selection, and, also have clear and immediate biomedical relevance, is that of metabolism. How we eat, and how we process and integrate the food we eat, is of obvious fitness relevance in the evolutionary and medical senses. It turns out that there is even variation in our saliva which is probably due to natural selection. The combination of diversity in human cuisine and susceptibility to the diseases of modern life indicate possibilities as to the relationship between past selection pressures and contemporary patterns of genetic variation. Of course one has to tread softly in this area, there are the inevitable confounds of environment, as well the unfortunate probability of any given locus being of small effect size in its influence on any given trait.

ResearchBlogging.orgA new paper in Genome Research reports a SNP which seems to have been subject to natural selection in Eurasians within the last 10,000 years. This variant is located within an exon on a gene, GIP, which produces peptides critical in the regulation of various metabolic pathways, in particular insulin response. A possible biomedical relevance to risk susceptibility is then explored subsequent to the evolutionary genomic preliminaries. Adaptive selection of an incretin gene in Eurasian populations:

Diversities in human physiology have been partially shaped by adaptation to natural environments and changing cultures. Recent genomic analyses have revealed single nucleotide polymorphisms (SNPs) that are associated with adaptations in immune responses, obvious changes in human body forms, or adaptations to extreme climates in select human populations. Here, we report that the human GIP locus was differentially selected among human populations based on the analysis of a nonsynonymous SNP (rs2291725). Comparative and functional analyses showed that the human GIP gene encodes a cryptic glucose-dependent insulinotropic polypeptide (GIP) isoform (GIP55S or GIP55G) that encompasses the SNP and is resistant to serum degradation relative to the known mature GIP peptide. Importantly, we found that GIP55G, which is encoded by the derived allele, exhibits a higher bioactivity compared with GIP55S, which is derived from the ancestral allele. Haplotype structure analysis suggests that the derived allele at rs2291725 arose to dominance in East Asians ∼8100 yr ago due to positive selection. The combined results suggested that rs2291725 represents a functional mutation and may contribute to the population genetics observation. Given that GIP signaling plays a critical role in homeostasis regulation at both the enteroinsular and enteroadipocyte axes, our study highlights the importance of understanding adaptations in energy-balance regulation in the face of the emerging diabetes and obesity epidemics.

This is a paper with several moving parts.

-There is genomics (the broad sweep of the genome)

-Genetics (a focus on a few genes and their consequences)

-Biochemistry

-And some allusion to epidemiology, as befits a paper which comes out of a medical department

The first observation is that rs2291725 differs a great deal across populations. As I said, it’s a SNP on an exon in GIP. Not only that, it’s nonsynonomous, which means that it’s in a position to change the structure and therefore function of the biochemical which the sequence is ultimately coding for. The T allele is the ancestral variant, while the C allele is the derived one. That means that C arose as a mutation against the background of T. There is a figure which shows the geographical distribution of the variance on this SNP from the HGDP data set in the paper, but I think the HGDP browser produces a crisper display, so here it is:

rs2291725.frqs

As you can see the ancestral allele is dominant in Africa. In several populations it is fixed. In contrast among non-African populations there’s quite a bit of variation. In East Asia the derived variant is at a high frequency, though not fixed. In West Eurasia and North Africa the two variants are at rough balance, more or less. Finally, in the New World the derived variant is found in appreciable proportions, but the ancestral variant of the SNP is found at much higher proportions than in other non-African populations. Seeing as how Amerindians derive from a branch of East Eurasians, common descent from an ancestor with the derived allele can not explain the frequency discrepancy. Interestingly the HGDP Melanesians have amongst the highest frequencies of the derived allele in the data set.

In any case, most of the analysis was not done with the HGDP sample, but with the first two phases of the HapMap. The marker density is richer in this sample, and obviously it is easier to compare a few populations than dozens. So the primary populations of comparison in this study were the Chinese + Japanese (ASN), Utah Whites (CEU), and Yoruba from Nigeria (YRI). It was immediately noticeable that when doing pairwise comparisons between two populations in the HapMap data set that the SNP of interest in GIP was exceptional in between population difference when set against other nonsynonymous SNPs. The chart below shows the SNP in red, with the full distribution curve of Fst (proportion of between population difference) illustrated by the bars in blue. rs2291725 is the top 0.5% of Fst difference between ASN and YRI.

dia2

The expected Fst between continental races is on the order of ~0.15. The ASN vs. YRI difference is far greater than that, and even more exceptional when you note the skew of the distribution. As it happens there’s HapMap3 data on this SNP as well. It doesn’t add much value to the HGDP, but does confirm the general findings:

gip1

Population descriptors:
ASW (A): African ancestry in Southwest USA
CEU (C): Utah residents with Northern and Western European ancestry from the CEPH collection
CHB (H): Han Chinese in Beijing, China
CHD (D): Chinese in Metropolitan Denver, Colorado
GIH (G): Gujarati Indians in Houston, Texas
JPT (J): Japanese in Tokyo, Japan
LWK (L): Luhya in Webuye, Kenya
MEX (M): Mexican ancestry in Los Angeles, California
MKK (K): Maasai in Kinyawa, Kenya
TSI (T): Tuscan in Italy
YRI (Y): Yoruban in Ibadan, Nigeria

Now that they’ve established between population variation at the SNP, what about the structure around the SNP? Remember, the SNP is one base pair. T in the ancestral state, C in the derived. The patterns of variation flanking the SNP in GIP can tell us a lot. What they found was this:

- Africans have several different haplotypes around the T allele. A haplotype is just a set of correlated markers

- The C allele in East Asians seem to be embedded within one haplotype, or set of markers

- There was a lot of linkage disequilibrium around the C allele in East Asians

In East Asians both EHH and iHS were consistent with, if not necessarily suggestive of, selection. A plausible scenario is that the C allele was subject to a powerful bout of natural selection recently, and the allele rose so rapidly in frequency that a selective sweep dragged along the flanking regions of the genome. This would homogenize the variance in that genic region within the population in question (East Asians), as the numerous other haplotypes would decline in proportion. To show the relationships of the various haplotypes within the three HapMap populations being analyzed here they produced an unrooted tree. Observe that the haplotype in which the derived variant is embedded has only Asians and Europeans, and is on a separate branch by itself:

diab3

I noted above that just because there is a lot of linkage disequilibrium and haplotype block structure in this region of the genome, it doesn’t necessarily mean that it was a target of natural selection. There may have been stochastic phenomenon which produced these results, and so our inference would be a false positive. To check for this they ran several models and simulations which varied demographic parameters under neutral (non-selective) conditions, and for the Asian sample the iHS scores were generally not as low as those for the SNP of interest. This does not “prove” that demography can not explain these results, but it does shift the probability more toward natural selection than before.

The circumstantial evidence presented above is that the derived allele rose to frequency relatively recently (in general LD decays rapidly over time, so these tests detect more recent selective or demographic events). They ran a simulation under neutral parameters, and for the frequency of the derived haplotype it would take 100-500,000 years for the various populations to reach the values which we see (starting from the initial mutant gene copy). The latter figure is outside the bounds of modern humanity, while the former probably pre-dates the ”Out of Africa” event. It is implausible that so much haplotype structure could be preserved over time, because recombination over the generations breaks apart associations between markers. Using the recombination rates, which would slowly degrade long haplotypes in the genome, the authors inferred that the C allele and its haplotype began to rise in frequency on the order of 12-2,000 years before the present.

Why would an allele rise to frequency within the past 10,000 years? The authors gave the game away in the abstract: humans shifted to different modes of primary production after the rise of agriculture. This is where the role of GIP in producing peptides which have a role in regulating our biochemistry is relevant. GIP is of a class of hormones found in the intestine called incretins:

Incretins are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating, even before blood glucose levels become elevated. They also slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying and may directly reduce food intake. As expected, they also inhibit glucagon release from the alpha cells of the Islets of Langerhans….

500px-Incretins_and_DPP_4_inhibitors.svgIncreased insulin reduces blood sugar. Diabetes is a malfunction of the insulin release mechanism, and so blood sugar begins to rise as individuals don’t uptake their glucose. Glucagon has the opposite effect, increasing blood sugar. But just because there is a change in a nonsynonymous position in an exonic region of a gene of relevance to the pathway, it doesn’t mean that that necessarily impacts the pathway which is illustrated to the left. And for natural selection to have any traction it needs to have an impact on some sort of concrete biological process (unless we’re talking intra-genomic competition of some sort).

It turns out that rs2291725 is actually just outside the primary coding region for the GIP peptide. For it to be a functional variant there needs to be more to the story. As it turns out, there are other less common variants which ware modified by changes at this SNP, GIP55S and GIP55G. The first is produced by the ancestral T allele, and the second by the derived C allele. GIP55S and GIP55G are also found in the intestine, though they only constitute a few percent of the total GIP.

gipactBut here’s where it gets really interesting: GIP55G exhibits more bioactivity over the long term. In other words it seems to be more potent the generic GIP or GIP55S, the ancestral variant. They’ve gone from supposition based on the functional significance of the broader gene, to a connection between the T→C transition over the last 10,000 years. As it turns out it may be that those with GIP55G would have a stronger insulin response, and so reduce blood sugar faster, than those without.

It doesn’t take a genius to figure out where there’re going with this. The relationship between insulin response and carbohydrates in our day and age is fraught. But we already suspect that carbs have reshaped the human genome through copy number variation in the amylase gene. It is interesting though that the derived variant has not fixed. That is, it hasn’t replaced the ancestral variant. This may be due to dominance, so that one copy is almost as efficacious as two, or, it may be due to balancing selection of some sort, which the authors suggest in the text. At this point it’s time to jump to the discussion and let the authors speak for themselves. They start out well:

Based on the gene age estimation and biochemical analyses, our study revealed a functional mutation that is associated with the selection of the GIP locus in East Asian populations ~8100 yr ago and the presence of a cryptic GIP isoform. Specifically, we showed that the inventory of human GIP peptides has recently diverged and that individuals could express three different combinations of GIP isoforms (GIP, GIP55S, and GIP55G) with distinct bioactivity profiles. Future study of how this phenotypic variation affects glucose and lipid homeostasis in response to different diets and of which physiological variations in humans can be attributed to prior gene–environmental interactions at the GIP locus is crucial to a better understanding of human adaptations in energy-balance regulation.

As I observed above many of the researchers have a biomedical background, and the NIH is funding this. The evolutionary anthropological findings, cautious as they are, are fascinating and of deep interest. But I don’t think this is going to go anywhere:

It was hypothesized by Neel almost 50 yr ago that mismatches between prior physiological adaptations and contemporary environments can lead to health risks because the ancestral variants that have been selected for the organism’s fitness or reproductive success may not be optimal for the individual’s health in the new environment…In support of this thrifty genotype hypothesis, a number of genes in humans and house mice have been implied to have coevolved with the emergence of agricultural societies…and a rapid shift in diets is associated with the detrimental effects on human survival in a number of human populations…Conceptually, the serum-resistant GIP55G carried by the GIP103C haplotype may have been beneficial for individuals who have unconstrained access to the food supply in many agricultural societies by preventing severe hyperglycemia. As selection pressure changed in these societies, the ancient GIP103T haplotype could have become a liability and conferred a loss of fitness in the new environment. In addition, we speculate that the selection of GIP in East Asians may contribute to the heterogeneity in the risk of diabetes among major ethnic groups at the present time….

Do you believe that the Han Chinese have had a surfeit of food compared to Africans over the past 10,000 years? Or compared to Europeans? Indians have had more food than Africans? The populations of the New World are in a food-poor environment? This doesn’t make any sense as an evolutionary explanation because the stable state for most of human history has been one of Malthusianism. A few people had a lot of food, ergo, the association of wealth with corpulence. Additionally, one can imagine that societies transitioning between modes of production would have a period when land would be in surplus and there was a lot of food. But for most of history life was grinding. This is simply an unbelievable story. Additionally, this SNP can’t explain most of the variation in diabetes. South Asians have the highest rates in the world, but they have appreciable proportions of the derived variant. I am of the CC (derived-derived) genotype myself (I justed checked on 23andMe), and I have a family risk of diabetes, so I know to ignore the relevance of these findings for myself when it comes to personal risk assessment.

There is probably not going to be one gene that explains diabetes, or obesity, etc. We already knew that, but there is a strange kabuki theater which goes on whereby research groups pretend as to the high significance of one locus, because how is it going to look to a granting agency that you’re out or explain ~1% of the variance in a trait for trivial predictive value? And yet usually they’re honest enough in the discussions to suggest that one finding needs to be integrated into a broader picture…as in the hundreds of other genes of interest!?!?!

This paper is fascinating as a work of human evolutionary history. They don’t have a good story, but they have results which need to be integrated into the bigger framework. But the paper is also a story of the culture of science today, driven by biomedical relevances which are often simply phantoms.

Citation: Chang CL, Cai JJ, Lo C, Amigo J, Park JI, & Hsu SY (2010). Adaptive selection of an incretin gene in Eurasian populations. Genome research PMID: 20978139

July 7, 2010

The short life expectancy of longevity genes (?)

Filed under: Genetics,Longevity,Medicine — Razib Khan @ 11:39 pm

When I first heard in the media there was a new study of longevity which had produced a model based on your SNP profile that was “77% accurate” as to whether you’d live to the age of 100 or not, I assumed this was confusion or distortion (perhaps The Daily Mail had broken embargo first and its spin was percolating around the mediasphere). But later I listened to one of the researchers on the radio, and though he seemed to want to tone down the certitude as to that prediction, he did not debunk the claim. Whatever the details, I did not believe that the model was that relevant to most people since very few are going to make it deep into their nineties in any case (I did have a grandfather who made it to 100 [in Bangladesh!], so my chance is presumably greater than the norm). The model would be moving you along the margins. Additionally, over the years it has paid off to be skeptical of the discovery of large effect genes for X, Y and Z. When the X, Y and Z has medical significance I’m even more skeptical, because the non-scientific biases within medical research seem to be really strong. There’s a lot of fame and money to be had. Some of the media were asking the researchers up front whether this might unlock the genetic “Fountain of Youth.” This is entrancing stuff.

So is this post from Dr. Daniel MacArthur, Serious flaws revealed in “longevity genes” study, warrants notice:

If the paper’s claims were true they would be truly remarkable. However, the general feeling from the GWAS community is that the identified associations are likely to be largely or even entirely artefactual, the result of failing to fully control for differences in the genotyping methods used in the cases and controls. The study used a mixture of two different genotyping platforms (albeit both made by Illumina) for their centenarians, while the control data was taken from an online database containing samples examined using multiple platforms. Disturbingly, similar potential genotyping bias also affects their replication cohort.

In the Newsweek piece I mentioned yesterday Kári Stefánsson has this to say about one of the platforms:

Kári Stefánsson, the Icelandic geneticist who founded deCode Genetics, knows something about the 610-Quad—his company has used it too. He says it has a strange and relevant quirk regarding two of the strongest variants linked to aging in the BU study, called rs1036819 and rs1455311. For any given gene, a person will have two “alleles,” or forms of DNA. In the vast majority of people, at the rs1036819 and rs1455311 locations in the genome, these pairs of alleles consist of one “minor” form and one “major” form. But the 610-Quad chip tends to see the wrong thing at those particular locations. It always identifies the “minor” form but not the “major” form, says Stefánsson—even if the latter really is present in the DNA, which it usually is. If you use the error-prone chip in more of your case group than your control group—as the BU researchers did—you’re going to see more errors in those cases. And because what you’re searching for is unusual patterns in your cases, you could very well mistake all those errors (i.e., false positives) for a genetic link that doesn’t actually exist.

Stefánsson says he is “convinced that the reported association between exceptional longevity and most of the 33” variants found in the Science study, including all the variants that other scientists hadn’t already found, “is due to genotyping problems.” He has one more piece of evidence. Given what he knows about the 610-Quad, he says he can reverse-engineer the math in the BU study and estimate what fraction of the centenarians were analyzed with that chip. His estimate is about 8 percent. The actual fraction, which wasn’t initially provided in the Science paper, is 10 percent, the BU researchers tell NEWSWEEK. That’s close, given that Stefánsson’s calculations look at just two of the variants found in the study and there may be similar problems with others.

Stefánsson recognizing one of the 150 SNPs as a problematic one is another red flag.  The effect sizes of the SNPs in the study seem really large, so that should make you curious as to what’s going on. Here’s a post from 23andMe suggesting we should be cautious of the results for that reason:

-A large study combining results of four genome-wide association studies of longevity was published in May in the Journals of Gerontology. That study found no associations meeting their pre-specified criteria for genome-wide significance. While they used a more inclusive phenotype (age 90 or older), it is surprising that there could be so many loci associated with survival to age 100 in the new study, some with very large effect sizes, yet none were found in the larger study from earlier this year.

23andMe applied the model (the SNPs) outlined in the paper and attempted to see if it had any utility in to their admittedly small sample within their own database. They found nothing of note:

We took a preliminary look in our customer data to see if the proposed SNP-based model described in Sebastiani et al. is predictive of exceptional longevity. A commonly used measure of test discrimination is to calculate how often, for a randomly selected case and control, a test correctly assigns a higher score to the case. This is known as the “c statistic” or “area under the curve”. The authors of the new study say their model scored a 0.93 for this statistic. But when we compared 134 23andMe customers with age ≥ 95 to more than 50,000 controls, we obtained a test statistic of 0.532, with a 95% confidence interval from 0.485 to 0.579. Using 27 customers with age ≥ 100, we get a value of 0.540, with a 95% confidence interval from 0.434 to 0.645. A random predictor of longevity would give a 0.5 on this scale, so based on our data, performance of this model is not significantly better than random. Even with our small sample size, we can also clearly exclude values as high as the published result of 0.93.

If you go back to Dr. MacArthur’s post he has a chart which indicates that even by eyeballing their are indications that the results in the Science paper were artifacts of the methodological limitations. Newsweek ends with this caution:

Still, one has to wonder how the paper wound up in Science, which, along with Nature, is the top basic-science journal in the world. Most laypeople would never catch a possible technical glitch like this—who reads the methods sections of papers this complicated, much less the supplemental material, where a lot of the clues to this mystery were?—but Science’s reviewers should have. It’s clear that the journal—which hasn’t yet responded to the concerns raised here—was excited to publish the paper, because it held a press conference last week and sent a representative to say as much.

This isn’t about the media. They didn’t have to sensationalize too much; the findings themselves if correct are moderately sensational.  But if Dr. Daniel MacArthur could spot something indicative of serious problems by scanning the supplements presumably it shouldn’t have made it through the review process without the issue being mooted and addressed. But then again, it’s medical genetics, and there’s a lot of pressure to find the roots of human morbidity and mortality. It’s a field where results like ALH 84001 abound. The heart wants what is wants. That’s why it’s nice to focus on less practical evolutionary genetic questions; no one really cares that much whether we’re descended from Neandertals. Right?

Note: And earlier post from Nature with more quotes from scientists who are skeptical of the findings. Also, after reading the posts I did read the original paper. Obviously I was cued to fixate on the particular issues highlighted above, but it is often rather illuminating to contrast the clear and spare summary presented to the public of findings to the numerous moving parts in the guts of the original paper.

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