Friday, December 23, 2005

Judicial activism, part one

Part One:  What they do

Let's do a thought experiment.  Imagine the First Amendment to the U.S. Constitution was just a little different:

Congress shall not paint stars on its bellies.

Now to you and me, the meaning is pretty plain.  There are no fuzzy points, no areas of contention. 

What if somebody gets tricky and asks about taxi drivers?  Our imaginary amendment says nothing about them.  Maybe another law somewhere says taxi drivers shall not wear stars on Thursdays.  Maybe not.  The point is:  it is not about taxi drivers or Thursdays.  It controls Congress.

Now if you were a U.S. federal judge, it is just as plain.  The Constitution exists to Protect People From Tyranny and Oppression.  No matter which rock Evil tries to hide under, it will be found and smashed.

So in this case, our fearless judges would discover that Americans have a natural right not to see star-bellied Congressmen.  The Founding Fathers would not have mentioned it at all if there wasn't a universal right that needed protecting.  All the circuit judges reading this nod their heads at this point.

And at this point, a justice of the Supreme Court would whip out his great, shining Chainsaw of Generalization.  For the right cannot be limited to only Congressmen.  What's the point, if the town council and postmen can go about with nasty stars?  To really have teeth, the right has to eliminate all government starifying.  Only then can people gaze freely on the starless public spaces, in this great free land between the two seas.

For the star would be a symbol of oppression and control, a tool of fundamentalist oppressors.  If the mayor put a big star on the town square, he might as well have sent a starry Senator Kennedy to belly dance in your living room—it's just that horrible.

So the people have to be protected by any means necessary.  A noble defense lawyer can find something star-shaped, help someone learn how offended they are by it, pay their court filing fees for them, and presto! a federal court will protect their rights.  Rights they may not have even known they had, until an officer of the court helped the victim discover them.

Of course, the First Amendment really says

Congress shall make no law respecting an establishment of religion.

Now once again, the meaning is pretty clear to you and me.  Unfortunately, once again it is also clear to our glorious federal defenders:  all governments everywhere must be completely cleansed of every trace of religious contamination.  Slapping a cross on the city seal causes such injury to someone (exactly what injury is never mentioned) that it must be remediated.


Wednesday, December 21, 2005

Good news for chronic migraine

This study looked at family history of vascular risks in migraineurs. Vascular risk factors tend to run in families, but are not easily measurable in younger migraineurs. Looking at older family members makes the risks easier to measure, and gives more accurate results (larger experimental sample). I find the following result particluarly interesting:

[Chronic migraine] patients were more likely to have a negative [family history] of stroke compared to other headache types, suggesting that [chronic migraine] is likely a neuronal disease rather than a vascular one.
This result is not unexpected. If continuous chronic migraine were caused by symptomatic vascular problems, we would expect a spectacular increase in vascular adverse events. (Like how a person with daily heart pain is living on borrowed time.)

Unfortunately, this study only compared different types of migraine to each other, so it does not tell us the absolute vascular risk caused by migraine. Researchers: always use a normal control arm! For only a little higher cost, you can give your study meaningful results.

Saturday, December 17, 2005

Public benefits of GMOs

A comment on this post provoked me to think about what benefits we are getting from genetically modified organisms (GMOs). A common claim is that while they might theoretically be good, all they really do so far is line the pockets of the agri-giants. My reply was that GMOs already give a lot of public benefits:

Consumer: Fewer chemical treatments have been applied to the foods they eat. Protein levels are higher because of reduced competition for nitrogen by weeds.

Economy: Higher crop yields drive farmers and farm product suppliers out of business, freeing their labor for other work and industries. (Well, this is good if you subscribe to the creative destruction theory of economics.)

Land: Less land needs to be under cultivation at any given point. This reduces topsoil loss and airborne dust, and permits land to be left fallow for longer. I suspect that it also allows less aggressive, and therefore environmentally friendlier, tilling to be used.

Pollution: More concentrated cultivation means less fertilizer is wasted, less fuel is used to power farm equipment, less pollution is produced by farm equipment with poor pollution controls, and so forth. Not only good for the environment, this also lowers prices of other products that compete for the same feedstocks, and reduces strategic dependence on unstable supplies (such as Arabia).

Public: Many of these purportedly-greedy agribusinesses are actually wholly-owned by the public. (And don't whine that most stock is owned by giant institutional investors, not the general public. Those institutions are the public's insurance and retirement piggy banks.)

Future developments: Research budgets come out of the margin, the gap between income and expenditures. When a profitable company increases their income by X%, they can afford to increase research funding by substantially more than X%. Monsanto, for instance, ploughs about 10% of revenue back into research, which is astonishing for a company that exists solely to put commodities on the shelves of Wal-Mart. (The benefits are not just theoretical. Agri profits paid for the development of soybeans whose oil can be used to replace trans fatty acids, which will have tremendous cardiovascular benefits for Americans.)

Security: More efficient crops mean less possibility of shortage during drought or pestilence.

Gravity Probe B data finishes collecting data

This actually happened back at the end of September, but it was not covered much in the news (or I missed it).

Einstein's theory of general relativity predicts that a spinning object produces slightly different gravity than a non-spinning one. (It is called frame dragging, in case you care.) Gravity Probe B is a satellite designed to measure this effect for the rotation of Earth. If the results are reliable, they will either confirm relativity or blow it out of the water.

In principle, you can measure it by just putting a test mass in orbit around Earth and watching its orbit. Unfortunately for scientists, the rotation-and-gravity effect is absurdly, ridiculously tiny. The test mass must be highly isolated from anything that might affect it, like a single grain of dust, or even just sunlight. (Seriously: sunlight exerts way too much pressure.)

The measurements must be made far more meticulously than even the normal standards for scientific instruments. The test masses are the best spheres ever made by man, polished to within a few dozen molecule-widths of perfection. The masses are spun at thousands of RPMs to magnify the rotation-and-gravity effect. They are kept in a very high vacuum so aerodynamic drag will not affect them. Their container is made of superconductor to keep out magnetic and electric fields. The surroundings are chilled to within a few degrees of absolute zero to keep thermal radiation pressure from doing much. The test masses travel in their own orbits without being touched by anything, meaning the satellite has to constantly adjust to keep them from bumping into the walls of the container.

In short, it is one of the most audacious and precise projects every carried out. And so far the engineering seems to have been a success.

Friday, December 16, 2005

Blocking the destruction of endocannabinoids

Ars Technica has a short article about URB597, a drug that prevents the enzyme fatty-acid amide hydrolase (FAAH) from working.

Well FAAH is the enzyme that degrades endocannabinoids (marijuana works by stimulating endocannabinoid receptors).  Blocking FAAH effectively amplifies the levels of naturally occurring endocannabinoids.  The increase caused by the drug should be proportional to what the body is already putting out.  This should give more gentle and targeted control than drugs like marijuana, which indiscriminantly stimulate all cannabinoid receptors.

A paper to be published in PNAS shows that URB597 is a potent antidepressant in several animal models, and that this is "prevented by the CB1 antagonist rimonabant" and "accompanied by increased brain anandamide levels" In plain English, it improves mood like marijuana, and is blocked by the same drugs that block other cannabinoids.  (It's usually impossible to tell which receptors a drug affects, so researchers administer known blockers and stimulators to find out by way of comparison.)

The abstract also says that the effects "are maintained upon repeated URB597 administration".  Good.  The drug doesn't "wear out" over time. Lots of good drugs crater because the body rapidly develops tolerance to them.

These results are of considerable interest to chronic pain patients.  Cannabinoids are known to affect pain, as shown by considerable anectdotal evidence and some controlled trials.  They are also famous for their ability to reduce nausea and increase appetite.  This is relevant to migraine because the disease process often has the opposite effect: spectacular nausea and food aversion (to the point that some sufferers need hospital treatment for dehydration).

The abstract for the paper also says "Unlike direct CB1 agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of Δ9-tetrahydrocannabinol in rats."  In plain English, it does not cause obvious addiction-related behavior in animals.  This is good because it means the prohibition industry might leave it alone.

The abstract mentions the drug rimonabant in passing. That's an interesting new drug that blocks CB1 receptors.  It seems to have some of the opposite effects as marijuana, in particular producing "anti-munchies". It therefore is promising for the treatment of obesity and diabetes.  I do worry that CB1 antagonism may have depressant side effects, which would be just terrible for folks who need to lose massive amounts of weight.

Irony... going to Walgreens and hearing the Rolling Stones' "Mother's Little Helper" playing on the radio.

Hmmm... that reminds me of the time I heard a Wal-Mart play Queen's "Fat Bottomed Girls". I am thinking that some employee was not allowed to choose the music after that.

Sunday, December 11, 2005

Activist "scientific" journal joins Merck pile-on

The New England Journal of Medicine has published a direly-worded Expression of Concern about a Merck paper on Vioxx's heart risks. They claim Merck withheld data from the paper, and insinuate that secret evidence shows Merck deleted it at the last moment before publication. They finish by saying "Taken together, these inaccuracies and deletions call into question the integrity of the data on cardiovascular events in this article. We have asked the authors to submit a correction to the Journal."

Sounds bad for evil ol' Merck, eh? Well have a look at the NEJM's own data:

Rofecoxib (Vioxx) to naproxen relative risk
Study Group Relative risk, 95% confidence range
Original data NEJM Allegations
Entire group 1.39 – 17.37 1.68 – 20.13
Aspirin indicated subgroup 1.65 – infinity 1.66 – infinity
Aspirin not indicated subgroup 0.63 – 10.02 0.91 – 12.78

There are some major problems here.

Problem 1: Confidence ranges as wide as the Grand Canyon. This is not surprising, since the study produced less than two dozen measurable events. The results are just too small to draw precise conclusions. About all you can say with any confidence is that Vioxx looks fairly scary.

Problem 2: Alleged missing data makes no clinical difference. No doctor said "Oh no! If I had known the relative risk as 20 instead of 17, I never would have prescribed the drug!" It makes no practical difference. The data show a clearly risky drug, with a few percent chance of being spectacularly dangerous.

Problem 3: Secret evidence. The NEJM claims "We determined from a computer diskette that some of these [relevant adverse cardiovascular] data were deleted from the VIGOR manuscript two days before it was initially submitted to the Journal on May 18, 2000." What diskette? Of what origin and chain of custody? Determined how? By whom? In accordance with which published forensic data analysis standards? The NEJM is not saying.

This is not science. It isn't even journalism.

Problem 4: Uncontrolled data. At least from what the NEJM is showing here, the original trial had no placebo arm. It only compared one drug with another, not with no drug treatment at all. Merck told the FDA that naproxen must have been protecting people against heart attacks, and that the more frequent rofecoxib events were just the underlying heart disease of the study group. Without a placebo subgroup, who's to know? Skeptical scientists, that's who. Crap like this would get a bad grade in undergraduate biology. The FDA and the original NEJM reviewers should have sent Merck back for a do-over.

Lies. Damn lies. Statistics. Medical trials without a placebo subgroup.

Problem 5: Activism, not accuracy. Speaking to the New York Times, one of the NEJM article's authors says

"They did not disclose all they knew," Dr. Curfman said. "There were serious negative consequences for the public health as a result of that."
Say what?! The original data showed Vioxx to probably be dangerous, and the alleged data makes no material difference in that conclusion. Furthermore, Curfman provides no evidence that the data were hidden from the FDA, or witheld from the Prescribing Information sheet.

The NEJM appears to be outpacing The Lancet in the political activism olympics. I hear the winner gets a gold-plated Sphincter Medallion.

UPDATE: One of Derek Lowe's commentors, which I somehow missed earlier, makes many of the same points:

So are calculations made "incorrect"? Only in a way that an innumerate reader would care about. ... I doubt this "Editorial" would have made it through peer review without changes. I wonder what process NEJM used to assess it before going ahead and publishing? And will they be reconsidering that process going forward?

Saturday, December 10, 2005

Goto for Python

Wow, how could I miss this? Somebody added goto to the Python programming language! Not just plain gotos, either, but real computed gotos as well. Unfortunately it was just an April Fools joke. Yes, I said unfortunately. try/except works well for most uses, but sometimes a good ol' fashioned goto really hits the spot. They also seem to have added comefrom, perhaps the most nefarious idea to ever be visited upon computer science.

Tuesday, December 06, 2005

Migraine prophylaxis with naratriptan

This study shows that naratriptan can be used daily for migraine prophylaxis to very good effect. Unfortunately, all the triptan vendors are chasing the lucrative acute treatment market, so prophylactic use would cost US$8 000/year.

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