When you treat you physicians like Dilbert, it’s Dilbert medicine you’ll get. As 3rd party payers and HMOs continue to divorce expertise from judgment, so results Dr. Dilbert: the highly specialized and well-educated yet ineffective nebbish masochist. American medicine sucks? The problem isn’t a lack of health care management. Insurance and health management organizations do not provide medicine; they “manage” it. You do not stagger into the swanky Blue Cross Blue Shield office lobby so that the receptionist will buzz down a squad of underwriters to stymie your hemorrhaging which you have tracked across their polished floor. You go… to a hospital. You can’t just magically create “medicine” on a spreadsheet. Medicine is physical capital, real labor, and decades of accumulated medical education and experience. More layers of pointy hair to “arbitrage payment” don’t serve patients, they delegate the “bother” of medical expertise and accountability to physicians (excuse me: “providers”) while assuming effective jurisprudence by controlling who gets paid, when, for what, and how.

For example: in the Helix BRCA CliniCast, Dr. Barbara Ward describes how she recommends a treatment as medically necessary, but her judgment is overridden by the insurance company, and without funding, the treatment is not feasible. Resigned, she exclaims she’ll appeal, but she’s just the surgical oncologist, who is she to question the medical judgment of some bureaucrat? Sorry Barb, you’ve been downgraded to “provider.” You’ll have to just wait for HQ to make any decision, just like the guy who installs my cable (though I’m sure he’s quite the coaxial expert, too.)

So, how exactly is adding more and more layers of management to manage less and less wealth supposed to “fix” medicine? Is this Soviet Russia? Is the problem that we “just need a more perfect model?” Or is the problem that “management pretends to pay us, so we pretend to work?” What else can physicians do but pretend when they have 8 minutes to see the patient and after another all nighter of filling out forms? And who’s problem is it if in a decade there will be a drastic shortage of qualified primary care physicians because “management” has made it no longer economically feasible? Not management’s, of course. The problem is that “the people” are lazy and greedy. No worries, they can be replaced. Don’t be such a whiner, Yugo Doctor will still get you from point A to B just fine, right?

Physicians are a specialized intellectual professionals who provide a necessary social service. So why do they tolerate treatment as “providers” by third-party payers and their proxy institutions? Why not simply bill hours at professional rates, just like a lawyer? One could require a retainer, the government provides a civil servants to provide service if its otherwise unavailable, physicians could self-organize into self-governed firms, social work is pro-bono, and the entire system is well understood, established and (maybe too) effective —by example— in the practice of law.

Yet, outrageously, somehow when a physician employs simple billable hours at professional rates… incurs a “crack down?” What kind of bizarro world is this?

Frankly, I had always hated insurance companies and HMOs out of principle because I’m a hater, and hating is what I do. But not until I actually sat down and physically did some real medical administration research did the true black stupid horror of the medical system strike me. There is no fixing this system. The only way out is to opt-out. That’s why I wholly support nationalized healthcare; I have full faith that it will be so corrupt and inept that people will be motivated to finally leave the system —”crack downs” regardless.

23andMe unofficially announced recently that it will be forming an institutional review board (IRB). IRBs are a necessary oversight committee for human biomedical research, so this development means that 23andMe is continuing to advance from its scrappy consumer novelty web service origins and towards responsible medical. Also, contrary to the fashionable pessimism due to the recent economy, the formation of an IRB suggests that 23andMe’s leadership anticipates its future operation for at least the next decade. I agree —particularly since 23andMe has a runway between “basically forever” and “forever” due to the demographics and personal aspirations of its founding team and investors.

I hope that these rumors are substantiated with an official announcement soon. Predictive medical information without corresponding medical accountability sets a toxic precedent for a systemic permission of consumer abuse. When efficacy is not enforced through medically actionable accountability, profiteers inundate the general public with bogus medical claims that divert resources from often more prosaic real health care. This abuse is particularly alarming because while American medicine is considered to be grossly expensive yet too often ineffective, Americans still spend a substantial fraction of health care dollars on alternative medicine which has no or little efficacy. Another “nutritional supplement” consumer marketing gold rush in genomic testing would be tragic, but a 23andMe IRB is a step in the right direction towards responsible genomic medicine.

Steve Murphy reports consternation regarding Helicos’ “5% total error rate.” I’m no expert (as is Daniel MacArthur at Genetic Future, I’ll run this by him [done]), but I think that “total” in this context means for the total read sequence, not per base pair. However, assuming that error is independent per read, the “5%” statistic isn’t that relevant because one can achieve any arbitrary confidence by re-running the read. “5%” is just an intermediate variable. The per read error could be 99% and hypothetically one could still have a viable test if reads were cheap and fast enough.

From the Helicos Press Release:

Initial commercial specifications for the Helicos^™ Genetic Analysis Platform were set at 50 Mb per hour; 10 Gb per run in 8 days. Early adopters can expect 8 million reads at length-of-read from 25 to 50 bases in each of the 50 flow cell channels utilized, totaling 400 million reads per run. Aftermarket costs are approximately $1.80 per megabase sequenced or $45 per million reads. Additionally, performance is independent of template sizes anywhere from 25 b to 8 Kb. The total error rate is less than or equal to 5%, with a competitive 0.5% substitution error rate. Further, the error rate is independent of the read length. The HeliScope Sequencer is capable of accurately sequencing samples with 20% to 80% GC content.

Scientific data presented at conferences throughout the third quarter included conclusive demonstration of HeliScope Sequencer performance exceeding 50 Mb per hour using three bacterial genomes of diverse genomic content with limited if any sequence content bias, as well as proof-of-concept on single molecule paired reads maintaining our simple, amplification-free sample prep on human placental RNA and a demonstration of digital gene expression performance demonstrating accuracy, high levels of reproducibility and quantitation.

The somewhat troubling statistic here is the size of the read (25 to 50 bases). These sequencers work by shredding many copies of a DNA molecule into small overlapping pieces, reading these pieces, and then reassembling the reads into a sequence using a statistical model and templates. Yes, each composite read piece may be near 100% accurate, but depending on the sequence to be reassembled (e.g. long repeats) it can be difficult to reassemble smaller read pieces with sequence-consistent high confidence. The bigger the read pieces are, and the more those pieces overlap, the better the pieces can be reassembled. Small read pieces are not as reliable or accurate in reassembly.

But, real story here seems to be that there is no story yet: this is an intra-industry release meant to demonstrate progress to customers and investors. I read it as set of selective statistics an industry salesman could use to favorably compare against competitor statistics —to be conveniently “corroborated” by the press. If Helicos had something to broadcast outside its industry’s bubble, Helicos would have published something like: “We can sequence the human genome (3Gb) in X days for Y dollars with Z accuracy. Yes, we to be used to provide medical advice in the specific ways outlined at LINK for details and caveats. Pre-order now!” I don’t see that.

Otherwise, outside the sequencing industry (e.g. the medical community, including Yale genetics), the answer to “How much do I pay you to sequence my genome, how long will it take, and how accurate will your report be?” is: It Depends. But, as Dilbert knows, “it depends” is tech-speak for “abandon all ye hope of a useful answer.” “Abandon all hope” is probably not the best attitude for  prime-time medical application.

There have been plenty of other posts here on Think Gene foretelling the failure of the DTC market, such as free microarray tests. The consensus is that for these companies to survive, they must enter the medical market.  Critics will say that while companies such as 23andme, Navigenics, and deCODE are just waiting for the right time to enter the medical market, I think there is a different reason why they haven’t entered this market: malpractice.

Let’s first examine the issues in pharmacogenomics with genetic testing. There’s a very well written academic paper by Gary Marchant titled Legal Pressures and Incentives for Personalized Medicine. Additionally, at Redorbit, Olga Pierce writes:

Thus far, lawsuits based on a failure to offer genetic testing before prescribing a drug have mainly targeted drug manufacturers’ deep pockets. But drug companies have circumvented legal problems by including information on genetics and the potential danger of the drugs in package inserts given to consumers with their medication.

That means doctors have become the new targets, Marchant said. It’s a short matter of time before we see a new wave of these cases. Juries are going to say ‘you should’ve done something different.’

But doctors are faced with a catch-22, he said. Most health insurance plans do not cover such genetic tests. If patients cannot afford them, the doctor must decide whether to risk malpractice allegations or simply not prescribe a potentially helpful medication.

Doctors are in a very difficult position, Marchant said.

Doctors’ general lack of training in genetics makes matters worse, he added. Anybody practicing medicine in the country in the next ten years has to understand genetics — or go out of practice.

Institutions and professional organizations can help by establishing clear guidelines for when genetic testing is required, he said, and medical schools should offer new doctors more genetics training.

Nonetheless, there will be a dangerous period for doctors, he said. It’s doctors that are going to bear a lot of the risk during the transition period.

So doctors are liable if they do not give a genetic test when one is available and it may help with prescribing medication. An example is Wafarin/Coumadin, which Dr. Steve Murphy talks about often at his blog, where people can have extremely adverse side effects if they have a particular genotype.

If a doctor did have the genetic data and still prescribed the medication, then it would be pretty clear grounds for malpractice.

Now imagine if a doctor or institution had access to a full microarray of genomic data (including high penetrance mutations). On the one hand, it would be great because if a doctor is prescribing Warfarin, he can easily check the genetic data on file to see if Warfarin is an appropriate medication for the patient. On the other hand, what about mutations that aren’t widely known yet but can be used to determine adverse reactions to drugs such as Warfarin?  If the data is on file, regardless of whether the doctor knows about the mutation, then he may be held liable for malpractice. Negligence could be argued.

This poses quite a problem for the current SNP microarray testing companies. Why would doctors get a whole genome scan which could potentially put them at higher risk for malpractice when they could simply order individual tests? It costs more, but it keeps them safer.

I now propose a simple solution: involve a third party. Say a doctor at a hospital orders a test for Warfarin. The cost of doing a microarray is essentially the same as doing a single genetic test, but the hospital doesn’t want all that data on file. Instead, a third party can do the test and instead only give the hospital access to the specific region that request. In addition to malpractice issues, the other reason for doing it this way is to reduce the cost of licensing fees; why pay the license fee for a BRCA1/2 test if it’s not actually needed? If another doctor later requests a BRCA1/2 test, it can be made available immediately without having to perform another test, and the patient or the patient’s insurance is billed accordingly.

This leaves the microarray DTC providers in quite a bind though. They spent significant resources to develop their genome browser, which is really what gives them their competitive advantage in the DTC market. However, this genome browser doesn’t help them in the medical arena, and in fact may even hurt them for the reasons stated above — information overload and malpractice liability from it.

A commenter at Half Sigma expresses a common sentiment in the software community regarding genetics:

Don’t get your knickers in a twist. Egg selection, sperm selection, genetic engineering, and bioengineering will fix this. If we didn’t have these coming technologies, we would be screwed.

I tend to keep politics out of Think Gene, but I have bad news for the libertarian-leaning technologists of the Internet alarmed by the obvious asymptotic exponential limits in the human population function. As they know, high social fitness (e.g. education) is inversely correlated with reproductive fitness. However, reproductive technologies will only exasperate that correlation because they make socially fit children more expensive. Thus, the stratification of social fitness will continue to accelerate.

First, a quick brief about human-directed genetic selection:

• People will genetically engineer their children —and themselves— when the technology is available and demonstrably effective. To disagree would be to claim that all people will never practice any genetic engineering, and that is absurd.
  
• People already “genetically engineer” their children naturally: it’s called “sexual selection.” It’s not an coincidence that you don’t simply pick a random name out of the phone book to have children. Also, this selection is and has always been very much socially directed —implicitly and explicitly. This is so obvious that maybe it’s not consciously apparent to some people, but think of this: do your parents care with whom you have children?
• Society has and continues to strongly select people based on their genetics. The far most obvious example is that children are almost always raised by their biological parents. More broad and obvious examples include university admissions and nepotism. Further, society is getting better at sorting people by abstract merits rather than by mere geographic or ethnic constraints. Obvious examples include standardized testing and Internet communities. There is some non-zero correlation between these abstract merits and genetics.
  
• Technologies to artificially select gametes by genetic material are already available, although their use today is largely limited to very obvious genetic selection criteria like sex chromosomes and critical monogenetic diseases. This technology is rapidly advancing as we continue to learn about the human genome.
• Socially selecting yourself —e.g. attending graduate school— delays reproduction by a few years. But (generously) assuming a population-wide equal lifetime reproductive fecundity, that’s no big deal, because everybody is having the same number of children, right? WRONG.
  
  This the compound interest formula. Increasing the number of years until one has children increases the exponent. There is an exponential difference in population rates based solely on years waited to have children. Intuitively, think when you’re 28, out of grad school, have saved some money, and are ready to start a family, the 1.2 kids born to the teen-pregnant couples are already only 8 years away from reproducing again. Assuming family A has 1.2 children at 28 and family B has 1.2 children at 18, starting with equal populations, family B will double in size compared to family A every 110 years. (This function is even more greatly exasperated if the reproduction rate for family B is higher. If family B has twice as many kids per person (2.4) as family A, then family B doubles every 15 years compared to family A). This is highly simplified, but note in reality, the situation is even worse. Assume that some children in family B, by some greater intellectual or motivational endowment, attend graduate school. Likewise, some children in family A get teen-pregnant and choose not to attend university like their parents. The net effect is that the ability and motivation to achieve intellectual pursuits increasingly necessary in our highly specialized society is biologically deselecting itself out of both families when compared to the total population.

Now that’s out of the way…

Reproductive technologies like genetic engineering make having children an even more expensive investment of wealth and time —but only for the most success-conscientious couples. A larger investment means that the period and rate of childbirth will continue stratify by one’s desire to invest in themselves and their family —especially for couples without extended family support.

Face it, the trend in civilized nations is radical non-directed social stratification. It’s better to accept this reality so that we can discuss and respond to it rationally rather than pretending that the world is one big “all men are created equal” family because it’s too scary to think about otherwise. “All men are created equal” is a pragmatic legal abstraction that has been socially successful the last several centuries. It’s not a physical description of reality.

Contrary to the hallmark of every critical journalistic piece about genetics, the future of inequality needs no neo-Hitler concocting blonde-hair, blue-eyed super genius babies in sterile reproductive camps. It only needs to increasingly make raising more successful children more expensive. I’m not aware of any significant counteracting trend.

It’s that magical time of the year again, and 23andMe’s new ancestry feature has helped me share with my dear, unassuming Midwest family what I get them every year: politically antagonistic, erudite scientific trivia! (The coolest thing about genetics is that leftist don’t believe race exists and rightists don’t believe evolution exists, so if you’re into genetics, you can antagonize your family in the heartland and your friends on the coasts! Science sure is fun.)

Screenshot:

My ancestry is half soviet satellite Valu-Pak  (Gzrezhzak, Alesnik), half dixie British. (Yates, Davis) I myself was born in Missouri and was raised in Ohio. From a tiny sampling of my DNA extracted from my spit: DOES RACE EXIST, AND IS IT BIOLOGICALLY DETERMINABLE?

Success. Of course, when I say “race,” I mean “ethnicity” or “ancestry” since race is an antiquated term unfortunately associated with too many non-scientific connotations.

Oh, also, Rubenstein says: “buy 23andMe.” Merry Christmas!

I’m writing a now too long research paper on gene patents, and I don’t have time to finish it right now. But here’s a dump of quick gene patent facts to tide over the community.

The case which enabled gene patents I believe is Parke-Davis & Co v. H.K. Mulford & Co. (1911) Here, at issue, was a patent for a purified adrenaline extracted from animal adrenal glands.  Judge Learned Hand held that while adrenaline indeed was a product of nature, the purified form which was the subject of the patent was a different creature.  Thus, the extraction created something new, something patentable.  So, it follows that the holder of this patent does not have the right to exclude people from using the naturally occurring adrenaline.  Only from the use of the extracted form.

Now with genes, I believe it is that when someone extracts a particular gene (like in PCR), under Parke-Davis, they are entitled to a patent of the extracted gene and the extracted process.

Note that patents are only the right to exclude, not an exclusive right to the inventor.

To get a patent, the inventor must also show some use for the gene.  In Parke-Davis, the patent holder showed sufficient therapeutic use for the extracted adrenaline to pass the utility requirement.   The same requirement will hold for those seeking a gene patent.  Prophetic uses are allowed, so long as they are correct in the end.

NOTE: mere utility as the subject of further scientific inquiry is NOT sufficient utility, per Brenner v. Manson.

Very interesting news today, as Japanese scientists published a paper in Neuron discussing the reconstruction of images directly from the human brain using fMRI.  It does seem like neurology is making true progress, despite the popular notion that “we can never understand the human brain.” The future consequences of research like this may be controversial, but it’s the inevitable price of progress. Pink Tentacle covered this story along with a more technical overview by Brain Windows.

Visual Image Reconstruction from Human Brain Activity using a Combination of Multiscale Local Image Decoders.
Yoichi Miyawaki, Hajime Uchida, Okito Yamashita, Masa-aki Sato, Yusuke Morito, Hiroki C. Tanabe, Norihiro Sadato, Yukiyasu Kamitani.
Neuron - 10 December 2008 (Vol. 60, Issue 5, pp. 915-929)