Leave Your Genome to Science

Here's a question: When people agree to donate their body to science, will their genome be part of the deal? And will that make people even less inclined to donate? Note: Google "leave your body to science" and three paid ads come up, including one for LifeLegacy.org, an organization that organizes and encourages whole body donation. Curiously, there's a link to "Testamonials". Uh, how is that possible?

The Seesaw of Risk

If it's not clear by now, I am an advocate of early intervention. It's such a simple premise towards disease treatment: the earlier you intervene, the better your chances of reducing - and even preventing - disease. That's true on an individual/clinical level, as well - and more importantly - on a population level (a little understood paradox of the health insurance industry, for instance, is that they perceive disease prevention to be cost prohibitive, since the average enrollee only stays in plan for a few years, too short a time to wield any profit on preventive medicine). The basic principle of early intervention is that you identify risks of disease, rather than wait for causes or symptoms. And one fascinating result of that principle is that we now have a range of diseases which are fundementally risks. Metabolic syndrome, which I've written about, is one example; high cholesterol is probably the paragon of risk-based disease.

By and large, the emergence of high cholesterol treatments - including statins - has been a boon to the fight against heart disease. In the US, about 10,000 lives a year are saved by statins, according to a recent study (aspirin, surprisingly, has helped save more than double that amount). This has led to demand from some quarters, particularly in the UK, that statins be sold over the counter - making them more available and more likely to save more lives.

Now it's important to remember that high cholesterol (or, more precisely, high LDL cholesterol and low HDL cholesterol) is just a risk of heart disease; it doesn't constitute any real disease - understood as progressive injury to the body - in itself. But that hasn't stopped people from making the misstatement that cholesterol itself is a "killer", or from outlining risks for developing high cholesterol (in other words, risks of risks of disease). Indeed, try to find out exactly what the risk of heart disease is from high cholesterol, and you'll likely be stymied as I have been for the past half hour. While the websites for the American Heart Association and the Mayo Clinic and WebMD all talk about cholesterol as a risk factor, they don't quantify it at all (is the risk 20% higher for heart disease? 40%? 80%?). UPDATE: Finally found it - the ATP III [PDF link], a 2004 NIH report on treatment for high blood cholesterol defines it thus, for LDL cholesterol levels over 190 in the "highest risk" category:

The category of highest risk consists of CHD and CHD risk equivalents. The latter carry a risk for major coronary events equal to that of established CHD, i.e., >20% per 10 years (i.e., more than 20 of 100 such individuals will develop CHD or have a recurrent CHD event within 10 years).

By comparison, the ATP III says people with no risk factors have a 10 year risk of less than 10%.

Statins reduce that risk significantly: a 2005 metastudy found that a 40-point reduction in LDL levels reduced a patient's risk of heart disease by 20%. This is where the math gets hard for an individual: If you had an LDL of 190 - and thus had a 20% risk of developing heart disease, and statins reduce your level to 150, does that mean you subtract 20% of the 20% - and thus you now have a 16% risk of developing heart disease? Or do you recalibrate your risk level from the ATP III? It's not clear to me.

My math troubles aside, these results have been hailed as dramatic, and have turned statins into the biggest blockbuster drug of the past decade (sales of statins run somewhere around $13 to $15 billion a year).

But: now there's a new wrinkle. A new study out today found that statin use is associated with slightly higher cancer rates. (The Journal of the American College of Cardiology, which published the study, is subscription only, so a thorough WebMD story is here).This study found association, not causation, so it's not clear that the increased cancer is due to the statins themselves. And again, I can't track down a specific figure for what "increased risk" means - it says 1 case of cancer per 1,000 patients, but given that the meta-study had 90,000 patients, that means only 90 cases were found, not enough, I'd gather, to create a bonafide increased relative risk figure.

So my point is this: It's great that we're moving into an era of risk-based medicine, where we start acting earlier and, overall, will no doubt save more lives and extend the quality of life for others. But this is fundementally a numbers game based on odds and percentages, and these aren't so easy to measure, grasp, or to compute. Indeed, we may be able to crunch them out for populations, but that doesn't necessarily mean anything to one patient facing personal decisions.

Play this out: Patient A has some condition B that elevates his risk of disease C by D percent. He takes drug E, which reduces his risk of disease C by F percent. But drug E increases his risk of disease G by H percent. What we want to know, really, is I - What is the net result? Have we made the patient healthier, or sicker? And has this battery of drugs and diagnoses improved his quality of life overall or reduced it?

In an age of algorithms and biostatistics and metaanalyses and databanks, there is the impression (the illusion?) that we are well on our way to figuring all this out - that these formulae are being cranked out and that in a few years we will have decisive numbers on all this. Me, I hope that's true. But I wouldn't bet my house on it.

What's the Status of GINA? An Update

As I talk to people about the future of medicine and the future of public health, vis a vis genetics, one big caveat that always comes up is that, in this grand future when we can tap into our genetic profiles, we must have some way to protect that information so that it's not used against us - particularly in employment and insurance. Esther Dyson, for instance, speaking at Fortune's iMeme conference last week, said that protecting our genetic privacy looms as among the biggest impediments to letting this genetic information flourish. If we're afraid to let it out, for fear of it turning against us, we'll never be able to act on or learn from the information (even if we have the means to see it for a mere $1,000). The surprising thing here is that there is, in fact, a solution in the works: The Genetic Information Non-Discrimination Act, or GINA - pending federal legislation that would prohibit employment and insurance discrimination based on your genetic profile. Surprising, because this is, to my recollection, one of the rare occasions when Congress is getting ahead of a problem. Even though genomic sequencing for the common man is years off, and even though genetic testing now is by and large infrequent and often inconclusive, it's clear that, assuming the scientists are right, we will eventually need some sort of protection in place. Indeed,  the lack of privacy protections may actually slow the emergence of this genetic future, because companies are wary to venture into genetic testing unprotected. Pharmaceutical companies, for instance, have found it difficult to do clinical trials for genetics related drugs because of the perceived risks of genetic information floating out there.

So Congress has been, for once, ahead of the game. The Senate on two occasions passed versions of GINA. This year there's been a ton of activity, as this play-by-play shows, culminating this April in a House vote of 420 to 3 to pass its own version of GINA. And since then....

...well, it's been awfully silent. Legislation is notoriously slow, but in this case, since I have had a close interest, and since the past few weeks have been especially rich in portent - James Watson's genome released, Craig Venter's various escapades, and so on - I was starting to get concerned that GINA would stall out, yet again, and that it would be tabled until the fall (when, with an election season brewing, who knows if it would get any traction).

So I put in a call today to Sharon Terry, head of the Genetic Alliance, a genetics advocacy group based in DC that's been very much involved in the creation of GINA. Long and short: She is extremely hopeful that GINA will be law in a matter of weeks - perhaps soon enough for the Genetic Alliance Gala on July 25. What's afoot, Terry says, is that the Senate should pass a version very much like the House version later this week. Then the House, rather than pass their own version and force a conference committee to hash out the differences, would simply authorize the Senate version. Then it's up to President Bush - who's already on record supporting GINA - to sign it. Presto, GINA is law.

But that's not the end of it. Having gotten GINA into law, Terry and the Alliance will then have the "reverse engineer everybody's thinking," as she puts it - meaning that having won the argument that there's a problem in need of a legislative solution, she will now have to make clear that the problem has been solved, and that the science that may've been held back can now flourish.

Now me, I've never been convinced that genetic privacy will be in practice all that much of an issue; like a lot of privacy concerns, I think it's often overblown. But as a policy matter, I absolutely think that GINA is necessary - the legal liabilities are just too great without some sort of protection, and to truly convince the masses that genetic medicine is an arena worth entering, they'll need to be convinced that there's no downside (the masses are necessary because with them comes data, and that's way more important than just knowing what your genome is on it's own).

And like many on the vanguard of genetic medicine, Terry is cognizant of the disconnect between the cutting edge science laying the groundwork of genetic medicine and the medical infrastructure that will need to deliver it. That there is still a huge chasm, and no law alone can close it.

What's the Point of a Biomarker? A Look at BRCA.

I've ranted a bit before about how confusing is the steady onslaught of genetic associations to disease. Every day there seems to be a new genetic tag for another disease. Some diseases, though, have very clear and well-established genetic associations. Among the most researched is the connection between breast cancer and mutated BRCA genes (typically called BRCA1 and BRCA2). The generally accepted statistic is that between 5 and 10 percent of women with breast cancer will carry an altered BRCA gene. According to the National Cancer Institute, women with an altered BRCA gene have three to seven times higher chance of developing breast cancer than those without (altered BRCA genes are also associated with other cancers, including male prostate cancer). Women who have BRCA1 or BRCA2 gene changes have between a 36% and 85% chance of developing breast cancer and between a 16% and 60% chance of developing ovarian cancer during their lifetimes.

These strong associations have made BRCA among the most researched genetic associations out there - a PubMed search for BRCA lists 776 papers. In turn, these associations means that BRCA tests are some of the most popular genetic tests out there - they're even being pitched directly to consumers. Indeed, they are for many the first taste of genetic profiling. The BRCA test, in many ways, is a peek at our medical futures, how we will, soon enough, be tested for a wide swath of genetic mutations (or presence/absence of genes, or specific combinations of genes, etc), that could indicate certain probabilities of developing certain diseases.

But for all that research and for however pervasive the tests may be, there's still a huge grey area around BRCA. The New England Journal of Medicine has a new paper that shows that the presence of an altered BRCA test does not, in fact, increase mortality among women with breast cancer. In other words, if you have breast cancer, just because you have a buggy BRCA gene doesn't mean that cancer is more lethal. It is, admittedly, a rather fine point, and may be small solace to women with breast cancer - it doesn't as far as I can tell devalue the core assocation between the gene and the disease.

But almost simultaneously, there's a recommendation published in the Journal of the American Medical Association to increase the use of BRCA genetic testing among women with a higher likelihood of developing breast cancer. I'm all for increased use of screening tools - provided that the accuracy (sensitivity/specificity) of those tools doesn't lead to a rash of false positives (or worse, false negatives). But an important part of the moral bargain of screening is that, if it detects disease, that it improve outcomes - that is, we should screen earlier when earlier detection leads to less disease. If knowledge doesn't afford better treatment, then we're creating a very ambiguous arena where people may know they face disease, but can't do anything about it. And ultimately, that's just making people worse off, not better.

Update: EyeonDNA has a nice riff on the ethics & utility of screening for BRCA here.

The Tenacious P (This Week's MMWR)

That's P as in "polio". This week the CDC's MMWR reports that worldwide polio rates were pretty much flat in from 2005 to 2006, at about 2,000 cases - this despite the WHO's Global Polio Eradication Initiative, which has set a date of 2010 for worldwide polio eradication. This 2010 date has been moved back several times, as the disease proves itself more tenacious than expected. The two-step-forward/one-step-back deadline history is rather fascinating, to me:

To be sure, there are far, far fewer cases of the disease than in the early 20th century, when it was a major worldwide killer (before Jonas Salk's vaccine was distributed in 1962, there were as many as 58,000 cases annually - mostly among children - in the US alone). And it has been eliminated from most countries of the world; 98 percent of all global cases are now found in India, Nigeria and Pakistan. But the fact remains that it is not so easy to actually eradicate disease; that is, to vanquish it from the face of the earth. (I point here to the CDC's definition of eradication versus elimination versus control). I've written about the trickiness of eradicating disease previously. The basic challenge seems to be a logistical one - even if we have the means to immunize effectively, can we ever deploy immunization so completely as to stop the disease from skipping towards a susceptible population? This is the difference, as the CDC's report this week makes clear, between polio eradication (which we aim for) and polio control (which we pretty much have). The greater challenges here are the stuff of health metrics, and are only now starting to garner systematic and direct attention. The Gates Foundation recently helped set up an Institute of Health Metrics at the University of Washington, recruiting Christopher Murray from Harvard to take the helm. I was speaking with Dr. Murray about these sort of basic logistical challenges earlier this year, and he's remarkably pragmatic and clear in laying out the challenges. "The more complex the treatment, the more difficult it is to implement it," he told me, which seems self-evident until you consider how complex many of our medical treatments in fact are. Consider the further challenge of exporting those to Nigeria and the Asian subcontinent, it's no surprise that a few thousand cases still escape our grasp.

Still, despite the statis that seems to have set in with polio eradication, there's a hopeful section in the CDC's discussion:

In theory if the right tools were available, all infectious diseases would be eradicable. In reality there are distinct biological features of the organisms and technical factors of dealing with them that make their potential eradicability more or less likely. Today's categorization of a disease as not eradicable can change completely tomorrow, either because research efforts are successful in developing new and effective intervention tools or because those presumed obstructions to eradicability that seemed important in theory prove capable of being overcome in practice.

This is very intriguing to me, because it boils down to an engineering problem - a problem that I think we are very close to solving, or at least improving upon. The right tools may be just around the corner: simple-to-use DNA diagnostics that can be deployed cheaply and broadly to allow much earlier detection of polio and other infectious diseases. As D.A. Henderson, the general behind the war on smallpox, makes clear, smallpox was ideal for eradication because it the physical symptoms made it easy to detect - the pox was evident relatively early in the disease cycle, and that give health care workers a clear signal to work against. Other infectious diseases - malaria, TB, polio - don't give off such a clear signal, at least to the naked eye. But with the right diagnostic tools, we can "see" polio and other diseases far earlier, and thus have a better chance at earlier intervention. That's the recipe for the end of disease.

The Former Surgeon General Sticks It to the White House

George Bush's former surgeon general told a House committee today that he was routinely muzzled from speaking out on public health issues by the White House.

On the one hand, no surprise: there's been no end of critique that this admininstration is hostile to science when it doesn't suit their politics. And he's not the first former official to complain once he's out from under their thumb.

On the other hand, though, it should be surprising: Richard Carmona served the president for four years. He stayed there as policies on stem cells, sex education, and other public health issues were determined. The telling quote:

in public health, as in a democracy, there is nothing worse than ignoring science, or marginalizing the voice of science for reasons driven by changing political winds.

Unfortunately, this will go nowhere, I bet. Had he resigned in protest last year, rather than quietly, he may have created enough news to force some sort of change in policy (or at least rhetoric). The surgeon general, despite being a toothless position politically, has great influence popularly. But he missed his chance.

Trivia question: Why is the surgeon general a general? Because he runs the U.S. Public Health Service, a uniformed service of the U.S. government, alongside the four armed forces and the U.S. Coast Guard. So who is the Surgeon General's boss? Bonus question: What is the other non-military uniformed service?

Crisis Management & Sicko

I've always been fascinated with the art of crisis management - how companies strategize and react publicly (and behind the scenes) to negative publicity. So even though this is going around, I thought it worth a link: an internal memo from BlueCross on how to deflect the criticism's of Michael Moore's new movie, Sicko.

I haven't seen the movie yet (new baby and all) so I won't comment on the accuracy or spin of the memo, or of the movie. But I do think it points up the very real split reality of health care in the US. On the one hand, we have the most advanced medical care in the world. On the other hand, we do not distribute that care equitably, liberally, or efficiently. On the one hand, we have a system (not really a system, of course, but a de facto structure) that does a pretty good job of taking care of people from birth until death - child and maternal mortality rates are low, and we pay great mind to elderly care, so that we may live as long as possible, without rationing. On the other hand, that system makes almost no concerted effort at preventive care or early treatment, where we could have the largest impact in saving and improving lives. This dichtomy makes health care a particularly difficult subject to get your arms around - there's always a clear and compelling case for exactly the opposite perspective. As this mildly misguided post from a Google employee makes clear, there is a case to be made for the good the health industry does. It's just not a very compelling one next to very human cases of woe and misery.

So while I think Moore is right and justified in assailing the health insurance industry for unfairness, I also think the insurance companies are justified in pursuing their mission - to provide reasonable amounts of care in a for-profit venture. The fact that this industry fails in the larger mission we expect of it - to ensure and deliver the absolute best available care to all people in all circumstances - isn't in fact their responsibility. That's a much greater role than the one they are legally obligated and structurally able to accomplish. That's a job for a larger government effort. As a health economist explained it to me: If there's ever a case to be made for market failure in capitalism, it's in health care.

Whoops. I guess I did have an opinion after all.

This Week in the MMWR: Suicide (Don't Do It)

A stunning little chart in this week's MMWR from the CDC. If you're between 18 and 25 years old, your chances of dying from homicide exceed your chances of dying by suicide. For all older age groups, suicide far exceeds the risk of homicide.

A couple other little observations from the chart: the suicide rate for those 65 to 74 is actually lower than for those 45 to 64. But that dip stops at 75, when the suicide rate peaks at more than 15 per 100,000. PDF of this week's MMWR

Coded Messages, Via DNA

Through the looking glass: A nice post in Wired Science, picking up on a New York Times story, that references a New York Times Magazine story, about a published piece of research, about... sending coded messages through DNA sequences.

The Perils of Hospital Borne Infection

Much in the news about methicillin-resistant Staphylococcus aureus, or MRSA. Seems this dangerous bug - which can cause fatal infections, and which loves the highly conducive atmosphere of a hospital - is 10 times more prevalent in hospitals than previously thought. The risk here is that these bacteria are hovering all over the place in hospitals, and have taken advantage of the highly sterilized environment to evolve ever more formidable strains. Meanwhile, hospitals are filled with people with compromised immune systems and open wounds who are particularly vulnerable to infection. If you're healthy, you could be exposed to these bacteria without any problem; our immune systems keep the bacteria in check. Indeed, many of us may have already been colonized with the bacteria - they're just sitting on our arms, and no Irish Spring will get rid of them. But they're no real threat, unless our immune systems somehow fall off guard or unless they somehow find a way in to more vulnerable tissue.

Two thoughts:

First, it reminds me of what's called The Necktie Problem. The best way to avoid staph is to get doctors and other providers to wash their hands. But there's one refuge for bacteria always dangling around, that gets very little cleaning - neckties. This became evident a couple years ago, after a study showed that half of doctors' neckties carried dangerous pathogens, including MRSA. Given the infrequent dry-cleaning of neckties, this has started a small movement among some (forward thinking? Sartorially lazy?) doctors to get rid of neckties altogether in hospitals. The lesson being that no matter how sterile an environment you may institutionalize, there are always little things that you'll overlook. (Another reason to favor a female doctor, too.)

Second, an anecdote that puts the problem into some relief. I happen to know this doctor who specializes in infectious diseases - in particular, he's an expert in MRSA. He recently had to have a pretty simple surgical procedure. But it required general anesthesia. His wife happens to be a surgeon at the hospital where he was getting his surgery. So given that he has expert knowledge in the risk of hospital-borne infections, and given that he was likely to have been colonized by MRSA because of his work, and given that he had special understanding of his hospital's surgical procedures, he was particularly concerned about his likely high risk for developing an infection following his surgery. His solution: a total body scrub with antibiotics. This is not routine procedure - to wipe down your entire body before going in for surgery. It's something most folks wouldn't even consider as a precaution. But like neckties, dangling there, once you think about it, it makes total sense. If you ask me, next time me or mine have to get a scheduled surgical procedure, we're definitely getting a cleansing rubdown ahead of time.