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Animated Brain. The brain is divided into the ...Image via Wikipedia A look at almost any gene expression pattern in the brain will most certainly confuse you. This is in contrast to functional imaging studies that often show that the brain is organized into neat, aesthetically pleasing functional circuits. Why don’t genes show similar neat expression patterns that reflect a common functional organization ? Some clues to this can be found in the recent paper, “A survey of genetic human cortical gene expression” by Myers and company (DOI). Their joint analysis of individual variation at the level of genome sequence (Affy 500K array) and mRNA-expression (Illumina Refseq-8 Expression BeadChip) shows that most of the correlations between gene sequence and gene expression are between genetic variants that are far away from the genes whose expression they are correlated with (so-called, trans, effects). The team found 433 SNP-transcript pairs (99 transcripts) that showed a significant specific empirical cis association and 16,701 SNP-transcript pairs (2,876 transcripts) that showed a significant trans association. This result is similar to a previous study using mice DOI that found that the expression of the mouse strain-specific genes was driven mainly by cis-acting regulatory elements, whereas the brain region-specific genes were mainly regulated by trans-acting regulators. Thus, it seems that a given non-coding snp variant may be more likely to influence expression outside its local (50kb) neighborhood than close by. The authors generously provide access to this important data for folks who would like to query candidate snps. Manga !

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DNA artistry or chicanery ?

$390 for a few restriction digests and gel pic. Impoverished grad students slaving over benches everywhere – I feel your pain.

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There is no doubt that -omics and digital-bio is improving healthcare, IF, you’re NOT one of the 50 million uninsured human beings in America who lack health insurance. As a fan of all things free-and-open, bioinformatic and health2.0, I was glad to read Timothy Stoltzfus Jost ‘s new book, Health Care at Risk: A Critique of the Consumer-Driven Movement. A review of the historical and economic foundations of the so-called ‘consumer-driven healthcare’ movement which is well underway (supported by leading candidates from both parties), Jost unpacks inefficiencies inherent to both private insurance systems (adverse selection‘sick people need NOT apply’) and to public systems (moral hazard and demand inducement – ‘hey dude, pass the twinkies and cigarettes, – no worries, I’ll just rely on my free healthcare’). The main arguments, from Jost, that stuck with me, are that the consumer-directed system, as it stands today, is one that is skewed to address the moral hazard conundrum, and this is not likely to resolve much of the current economic crisis since healthcare spending is distributed very asymmetrically (a tiny fraction of very sick people account for most of spending). Indeed, Jost suggests the current consumer-directed healthcare movement (pass off the first $5,000 spending to the consumer) is likely to make matters worse before they get better. While sobering, the book may prompt a redoubling of the focus of the many free-and-open bioinformatic and health2.0 efforts working to enhance care and access for all.

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United States Supreme Court
Image by onecle via Flickr

I much enjoyed the June 15th podcast “Blame it on my genes” hosted at the New York Academy of Sciences. Here, Professor Paul Appelbaum lays out a biological framework for behavioral genetics wherein genes influence an individual’s sensitivity to experience in ways that predispose or insulate them from illness. As the basic science begins to map specific (gene x environment) examples, how, then, might this knowledge play out in the justice system where it could be used in “determinations of culpability?” Indeed, as covered by Professor Appelbaum, our justice system allows individuals to be excused from culpability when they are incapacitated (insanity defense) or via automatism (a sleepwalker commits a crime but is not consciously aware of it). Can, or should, genetic background be used in this way (a genetic determinism defense)? Professor Appelbaum reviews a key Supreme Court ruling from “Robinson v. California” citing the opinions of Justice Hugo Black that recognize that just because someone is influenced by causal factors, does not mean that that person cannot choose rationally. This opinion is based on the principle of compatibilism (free will and determinism are compatible) which apparently is rooted in an ancient school of Greek philosophers. Nevertheless, there is a lot of action in the lower courts where genetic evidence is being proffered to mitigate or lessen culpability – interesting times ahead. Perhaps the judiciary is already subscribed to “The DNA Network!”

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New York Times reporter Andrew Pollack covers recent evolutions in the DNA synthesis business in his September 12 article, “How Do You Like Your Genes? Biofabs Take Orders.” Apparently, the traditional high-school-science-lab-methods for cutting and pasting stretches of DNA have been replaced by “biofabs” – correction – a “biofab industry” complete with consultants and marketing research firms. The DNA2.0 website even has an ominous “biosecurity compliance” message (just the kind of goofy touch a consultant would come up with) noting that all orders are screened against the CDC list of “select agents.” Am I missing something ? The chemical mis-incorporation error in DNA synthesis is seriously problematic and, as noted in the article, the error rates for long synthetic sequences is undesirable to put it mildly. Seems to me you’d have to sequence and re-sequence a multitude of these commercially purchased clones to be sure they contained the correct sequence. I imagine many a grad student, using traditional cloning and mutagenesis methods, would have easily finished the cutting and pasting long before then.

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BBC Bush House in London
Image by ➨ Redvers via Flickr

As reported on the BBC, a recent call by Lord Justice Sedley, for universal inclusion (tourists too) in Great Britain’s national DNA database, has fanned longstanding civil rights debates. Given that the national DNA database carries disproportionate levels of ethnic minorities, it hardly seems fair to search or use the database within a legal framework or presumption that its contents generalize to the UK population at large. Some have concluded that there is much more genetic variation within ethnic and racial groups than between groups, making the ethnic composition of the database, a non-issue. In contrast, the article (free on Pubmed central) , “Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies,” led by Neil Risch and Nicholas Schork find that when many, many markers are used, clustering algorithms can reveal a strong correspondence between self-reported ethnicity and genetic background. This article was a good jumping-off point for me to learn more about this complex issue. I think its not to soon for me to start rehearsing what I’ll say to the cops when they pull me over for driving with an undesirable allele.

RELATED UPDATE … story on how US government insiders/lobbyists abuse public monies set aside for DNA testing.

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Just quickly plugging the various feeds and discussions from the recent Health 2.0 conference. Thanks to the facebook group, folks like me, who did not attend, are getting great insights into the emerging issues in this exciting area. Doesn’t seem like too long before the open, consumer-directed, health management & care model is seamlessly knitted together with ‘omics’ of all molecular weights!

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Health care for all protest outside health ins...
Image by Steve Rhodes via Flickr

I much enjoyed the recent article, “Do Not Ask or Do Not Answer” in the August 25th Economist. As genetic data begins to trickle into the hands of consumers, the debate on genetic privacy grows more intense. On the one hand, the article notes that the SRY gene has long been used to price insurance (its the gene that determines the male vs. female pathway during embryonic development – sorry males) and that a look at one’s parents and siblings gives a fairly decent sense of one’s genetic liabilities. On the other hand, the article notes a study showing that folks who find they carry a potent Alzheimer’s risk gene are more likely to purchase extra health insurance – thus out-gaming the insurance industry to their discontent. Both hands having acknowledged the disconnect, the article turns to the search for new financial strategies for the future when consumers possess detailed knowledge of their own genomes (speaking of which, take a moment to browse Jim Watson’s genome). Some of the solutions noted were a form of compulsory universal coverage where neither side can outgame the other, HSA’s where out-of-pocket expenses are paid from individual tax free investment account and other new business models such as provided by RedBrick Health where benefits are maximized by optimizing participants behavior. The science is moving fast. Will the health insurance markets keep up?

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Navigenics
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I’m not sure how they will compete with the open community effort of the Personal Genome Project, but they do have a very slick commercial. Check out Navigenics and you’ll feel your saliva start to flow !

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If I may shill for the corporate medical industrial complex for a moment … I much enjoyed the video interviews found at the Corporate Research Group. Regina Herzlinger predicts universal coverage, but not a single-payer system – rather a system where consumers have choices. How to decide which plan to chose ???

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Its hard not to gawk at the sub-prime mortgage spectacle these days … seems like there are limits to borrowing – who’d a thunk? I was struck reading the news of one fund, Global Alpha, a quantitative strategy fund run by the elite Goldman Sachs firm. Wow, if the brightest of the bright can stumble, I suppose no one will escape unscathed. In any case, the name of the fund ‘alpha‘ – refers to an aspect of the capital asset pricing model (the y intercept) that accounts for endogenous, organic growth of an asset, instead of growth driven by an overall rising marketplace (this type of illusory growth is denoted by beta). I’m not a successful investor, but the ability to identify sources of alpha seems like an important skill.

Which eventually got me wondering … where is the alpha in healthcare? What drives organic growth of the for-profit sector of the healthcare industrial complex? Creativity? New technology? Efficient use of technology? Demographic shifts? Cost-cutting and adverse selection (think Sicko by Michael Moore)? I suppose all of the above.

But, in some ways, the concept of alpha as embodied in the CAPM doesn’t seem to apply quite right … I mean, if we’re doing a great job helping folks stay healthy, shouldn’t that reduce the demand for services? Where’s the growth (alpha) in that?

What business model generates a common benefit such as health and the type of financial alpha needed to attract investors?

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David Leonhardt’s recent New York Times article “Free Lunch on Health? Think Again” on the economics of preventative medicine suggests the cost of preventative care for the vast majority of healthy individuals does not save money in the long run. The argument seems to go something like … most of the cost of healthcare goes toward a small percent of very sick people and that spending on preventative care does not do much to reduce the size of this already small group. It seems that spending a ‘little on a lot’ of healthy people is equivalent to spending a ‘lot on a little’ group of people.

This seems to me to be one of the big challenges for personalized medicine. How will bio-marker and IT-technologies be deployed to save money? Perhaps when it is cheap, reliable, trustworthy, consumer-friendly and useful enough to encourage individuals to get involved (ie. rewards consumers for paying out of their own pockets) ? Hmmm.

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A statue of Asclepius. The Glypotek, Copenhagen.
Image via Wikipedia

My wife was recently unfortunate to spill hot soup on her hand and ended up with a pretty uncomfortable set of 2nd degree burns. At our fingertips (mine anyway) we had easy online access to guidelines for pain management and infection prevention. The next day at work, she was able to see a company-sponsored nurse practitioner who cleaned, redressed and provided a prescription for burn cream. Only after the smoke cleared (or soup as it were) did we realize she was going to be OK and that we had paid $0 so far with a $10 co-pay coming for the burn cream. At dinner that night (we stuck with cold chicken salad) we each wondered uneasily whether we should have, or should think of, going to see a doctor. “Wouldn’t that be best?” “But you seem to have gotten such good care already.” The conundrum reminded me of Andy Kessler‘s book, The End of Medicine, where he becomes a human guinea pig and explores all sorts of medical diagnostics technology and also wonders how much longer people will really need doctors. We’re not as brave as Mr. Kessler, but are certainly wondering how far the consumer revolution can go in healthcare. For the time being, no more soup.

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An image of a 1901 examination in the faculty ...
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I much enjoyed Helen Mayberg’s October 13th podcast, “Paths to Recovery in Major Depression: Insights from Functional Neuroimaging” hosted by Science & the City, the webzine of the NY Academy of Science. One comment that stuck with me was her mention of ‘brain-based algorithms’ for the diagnosis and treatment of mental illness. Indeed, from her talk, there are many brain regions involved in the regulation of mood and that individuals who experience depression may show poor activity in any or all of these brain regions. Also, Dr. Mayberg shows that these various brain regions may be more or less responsive to drug- vs. talk-based therapies. This seems like a major step forward in personalized medicine in psychiatry and perhaps might be augmented by other biomarkers. Presently, scanning is somewhat cumbersome relative to current drug-trial-and-error regimens, but the benefits of recovery far, far outweigh the costs of a lifetime of chronic illness.

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In, The New Financial Order, professor Robert Shiller offers an in-depth analysis of how finance can and should be used to improve the human condition. By appropriately adapting financial instruments with risk, the consequences of many of life’s sudden shocks (natural disaster, loss of job, health crisis etc.) are readily ameliorated. Although he does not cover health insurance directly, his suggestions on how to better manage other types of risk point to an alternative viewpoint … away from the polarized “universal coverage” vs. “consumer-driven private coverage” debate. New bioinformatic strategies for managing health risk could readily be linked to financial instruments that more efficiently provide buffering to the economic consequences of illness.

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Harvard University
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Christopher Rowland gives a great perspective on the new venture fund at the Harvard Partners Healthcare system. If you want a peek at the future of personalized medicine, check out the Partners Center for Genetics and Genomics – where basic research is seamlessly integrated with clinical care. I attended their first annual meeting in 2005 and took home a lot to think about. This year’s meeting features Regina Herzlinger, who will discuss economic framework issues. I wonder if the Partners system is adopting or experimenting with new payor models … certainly the new venture fund will support research, but what about everyday clinical care?

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Mike Wigler’s team at Cold Spring Harbor Labs finds that spontaneous mutations are more prevalent in patients with autism than in patients with a first-degree relative also with autism. Perhaps the comparative genomic hybridization methods applied in this case will prove useful in sifting our spontaneous vs. ancestral forms of genetic variation in other diseases and mental disorders. Will males be assessed for rates of spontaneous mutation someday?

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I much enjoyed listening to the remarks of James R. Knickman, President and Chief Executive Officer, New York State Health Foundation. He reviewed some highlights of his career and the inner thoughts processes of non-profit foundations taking on complex problems. One particular topic he emphasized is the interest that foundations have in better understanding how new technology will alter the healthcare landscape.

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