The Futile Cycle

Via Ars Technica, there’s apparently a new database online called Deja Vu, which catalogues duplicate (or near duplicate) entries in MEDLINE, using an algorithm very similar to BLAST.

The majority of the entries retained in the database seem to be cases of outright plagiarism. Going through a few of the entries is like dredging the bottoms of the academic pool; most of the journals are pretty obscure or quite poor in quality, and I bet most of the authors are pretty unknown, too. It’s a strange world down in the pits…

Boston’s Mayor Thomas Menino apparently thinks that in-store health clinics (such as MinuteClinic) are unethical because they (gasp) make money off of sick people!

Wait, so what about pharmaceutical companies, medical device manufacturers, health insurance companies, doctors, nurses, ambulance workers, hospital staffers, and scientists who do research on clinical diseases (among others)? Maybe they shouldn’t be making money either! That would really encourage them to succeed in helping others!

And farmers shouldn’t be driven by profits, because they’re making money off of hungry people! And homebuilders shouldn’t be driven by profits, because they’re making money off of people looking for shelter!

To think that Boston would have a mayor so economically and morally illiterate.

There’s been a lot of media hullaballoo about the whole creation of human stem cells from skin cells, which is really just a confirmation of the research from last year on mice.

For some reason, some people, like this Washington Post editorialist, seems to think that this research side-steps the whole embryonic stem cell morality debate, that it “vindicates” George Bush’s decision to fight embryonic stem cell research.

It doesn’t.

The stem cell research from mice showed that these “created” stem cells can grow to become a whole embryo and organism. Let’s assume for a moment that in this respect, human biology is similar to mouse biology (it’s not far-fetched). If the newly created stem cell can grow to be a new person, doesn’t that mean it has a “soul”? So, then is it bad to do research on such a cell?

If, theoretically, this technology is perfect and can actually transform a skin cell to a good stem cell, then that stem cell would be no different from an embryonic stem cell, and all the same morality rules apply here (regardless of whether you are for or against it). This isn’t some sort of magic morality bullet. No ethical dilemmas are resolved here. You can’t support this sort of research and be against embryonic stem cell research, because this is embryonic stem cell research.

I don’t normally delve into ethics that much, because I don’t think most people share my eclectic set of reasonings, but when I saw the comments on this Crooked Timber post on the economics of the death penalty, I decided I’ve got to say something. I am not an economist, but I am a scientist, and science is as science does, so I’m going to comment on this from the point of view of a scientist.

One thing I saw quite often was people saying, “Economists always assume that people are rational, but that’s obviously not realistic!”

This is misleading! Economists define “rational” differently from the normal word, just like how every other field has its own jargon (”text” in literary studies, for example, doesn’t mean “written words”, but any human-produced work that can be analyzed; “energy” in physics doesn’t mean the same thing that normal people mean, but rather the capacity to accelerate a mass (or counteract an opposing force) over a distance).

In any case, when economists say “rational”, they mean someone who has some sort of internal set of goals and attains them. A “rational” person responds to incentives in ways that maximize how much they get what they want. So, if a person wants to not die, they’ll avoid things that might kill them. The goals can change over time (an old man has different goals from a toddler), and from person to person (Bill Gates obviously has different goals from Brittany Spears, which led to their different decisions in life). Economists tend to muddy the jargon more and talk about “utility”, but that has nothing to do with money, in general. “Utility” is just “how much the person has reached their personal goals.” So, in a sense, a person’s ultimate goal is to get what they want, which is kind of logically redundant.

This hypothesis is pretty good! People want things, and they do things to get them. Simple! They want to be happy, or maybe they’re hugely emo and want to be sad. Maybe they’re masochists and want to feel pain. Maybe they’re ultra-patriots and so want to die for their country. Maybe they want fame, or maybe they want money. These are all perfectly rational reasons; the key is just finding out the underlying “want.” Everyone is motivated by something; it’s hard to think of someone who isn’t. And people respond to incentives based on their wants.

Instead, most of the problems with economics come from economists trying to get from looking at individuals to groups of individuals, because it’s very hard to analyze even one person; more than one is almost impossible to do in any detail. (Studying just one individual in really great detail is called a “biography”, and economists generally want to study how most people work in general). Often, for the sake of simplicity, economists assume that individuals are more or less similar, or that they vary only along very specific characteristics. This is obviously not true, but the assumptions can be useful and good enough for the particular thing they’re studying. The assumptions can break down, but it’s not because economists assumed that people were “rational”; it’s because a particular economist assumes that individuals are motivated by the same things.

So, saying “people aren’t rational” isn’t a good criticism of economics. People are pretty rational. It’s the other assumptions on top, the “useful approximations”, that make the theories sometimes a little shaky.

Via Medpundit, an article in Scientific American arguing against race-based medicine. I spoke about this on an aside in a post a few days ago, but now I feel like I have to respond to the Scientific American article. Note that I’m not defending BiDil here, but the concept of race-based medicine in general.

I don’t think the trend for race or ethnicity targeted drugs is a bad thing, overall, because first, we wouldn’t have a shortage of new drugs for everyone, since drug companies would only try for subpopulation-targeted drugs in a case where the drug has failed in a larger population. They want profits; they’re not going to limit the scope of any drug to a subpopulation — race-based or genetics-based or whatever — unless they had no choice; just look at how much they try to expand the indications of already approved drugs. And research produces so many drugs that fail clinical trials anyway that it might as well behoove industry to try drugs on sub-populations, since they’ve brought the drugs so far through the clinical process. So nothing to worry about on the economic side of things.

Secondly, taking race into account is better than not doing so, I think. It is simply wrong and counter-productive to claim that people can’t be grouped into ethnicity based on genetic polymorphisms. There are strong sub-population differences on polymorphisms of drug metabolizing enzymes, so what is toxic to one group may not be to the other. And saying that only 10 drugs or so have evidence to back up race-based indications doesn’t mean that we won’t see more in the future, now that more biological understanding is coming out about such things. But until personal genome sequencing and profiling becomes a lot less expensive and a lot faster than it is now, ethnicity, or even race, is a better substitute than nothing. After all, humans have, on a population scale, very homogeneous genetics, and the variation from continent to continent is pretty clear, with minor exceptions, so ethnicity is a valid and easily detectable, though crude, genetic marker. (Ironically, “black”, which is what BiDil was approved for, is probably the crudest and most meaningless sub-population indicator, since Africa has the most diverse genetic variation in the world.)

I do, however, hope that the FDA does not go lax with its requirements of efficacy. After all, race-targeted or not, the drug still has to work. I don’t believe that a head-to-head of one race versus another would be strictly necessary before approval of a drug, since that brings in ethical issues (testing a drug in populations where researchers expect the drug to fail). Anyway, if a drug really is effective in a larger population, post-approval clinical trials would be a lot easier to test, as they would already have gone through the three previous trials for efficacy and toxicity, and so it would be advantageous to allow the drug company to seek approval based on a limited subset first.

Basically, I see race-based or ethnicity-based medicine as part of the whole “personalized medicine” endeavor. Even though it’s crude, it’s still the first step, and it’s what we have to work with right now. We have drugs targeted based on age and sex already, and biologists very well know that age from birth is just a surrogate for “real” aging, and sex is just a surrogate for “real” hormonal levels, developmental history, and so on. Until we have better biological markers, age, sex, and even race and ethnicity, are good starting points for tailoring medicine to each person. We already do it, so why not with pharmaceuticals, too?

UPDATE: A nice New York Times article on natural selection on human subpopulations.

For some reason, today I got to thinking about Bill Clinton’s class day speech at my graduation, where he kept repeating that humans are essentially 99.9% genetically identical; he used it to demonstrate why we shouldn’t emphasize our differences, but instead our similarities and find our connections. It’s an admirable moral goal, anyway, from a political point of view.

But if you look around, it’s relatively easy to find patterns that can roughly categorize people into races. I am Asian. It’s very easy to tell, from my hair color, my skin color, and the bone structure of my face. I’m a bit of a lightweight when it comes to alcohol, and I get that “Asian glow” after a drink or two. Some of my friends are very, very white. Some are Hispanic, some are African-American, some are Middle-Eastern. We can see all this polymorphism, so clearly the 0.1% does make a very big biological difference. After all, genetically we are something like 98% similar to chimpanzees, and yet we see huge differences. 0.1% of 3 billion bases is still 3 million bases.

So I looked around on the internet, and found this old, but wonderful, PLoS interview with Neil Risch, a population geneticist, who in 2002 published a refutation of an NEJM opinion article dismissing the clinical relevance of race. So really, that whole 99.9% thing is a bit misleading, since that 0.1% matters a great deal. So why mention genetics at all? Genetics has no real relevance for big-picture global issues of politics, war and peace, and all that, or for social issues on the level of being kind to each other.

And really, there’s no need to make that sort of weak genetic argument. You can look around and see for yourself that humans are pretty much similar. Everyone is born on basically the same pattern, with mothers and fathers, relatives, with mostly four limbs, two eyes, a nose and mouth, with a brain that loves, a mouth that talks, a heart that pumps, hands that grasp. A smile is a smile in every culture, a laugh is a laugh. There are variations on this theme, especially with modern medicine and technology, but mostly people are the same. We don’t need the human genome project to tell us that. Basing your ethical tenets on really shallow inferences from biology is usually not a good idea. Leave biology for biology and medicine, and just look around.

On the BBC, Israeli scientists try to circumvent chemotherapeutic sterility for girls with cancer. Essentially, the problem is that little girls with cancer can generally be cured with chemotherapy, but the aggressive regimes can sometimes leave the girls sterile. Thus, what the scientists did was isolate (surgically) unmatured oocytes and chemically induce them to mature, turning into eggs, which can be frozen to be used for in vitro fertilization (IVF) later in the girl’s life. An interesting idea, essentially “time-shifting” the eggs.

Anyway, they have a strange quote from an activist, Josephine Quintavalle, who demonstrates that she doesn’t know biology very well:

Josephine Quintavalle, of Comment on Reproductive Ethics expressed concern that if the eggs were donated to a woman of childbearing age, a resulting child could have a biological mother who was only a few years older. She said: “Are we going to end up with a child who has a mother who is just six years older? What happens if the child dies? Could the eggs be donated to someone else?

In case Ms. Quintavalle doesn’t realize, the current model of egg maturation in humans is that eggs essentially remain dormant, and usually only one matures at a time during each menstrual cycle (if more than one matures, it can lead to fraternal twins, triplets, etc.). Which means that a woman’s eggs in her ovaries haven’t aged very much compared to the woman herself, anyway.

To put it another way, let’s say someone donates eggs, and they sit for 100 years until someone else uses them for IVF. Assuming the science can actually do that, is it wrong that the “biological mother” (i.e. the egg donor) might be some 120 years older than the child? It’s not really any different (from an ethical point of view) from having the egg donor be a 5-year-old. Eggs are eggs, as long as they’ve matured properly. Now, there are plenty of objections one can make on the biological viability of the eggs, or the ethics of creating life by a procedure that may or may not lead to unexpected health consequences. This objection seems pretty groundless.

Strange that an activist on “reproductive ethics” would demonstrate so little knowledge of human biology. Really, what Ms. Quintavalle is exhibiting is nothing more than being squeemish:

I feel uncomfortable about this development.

That’s really the only thing she’s correct about.

There is a really great post and discussion on Marginal Revolution on a book, Money Driven Medicine (by Maggie Mahar) about the source of the spiraling costs in American health care that don’t seem to improve patient health at all. The best part is the comments, I think. There are some good commenters, and then the author comes to respond to some of their questions.

I really like this part of a comment from Yancey Ward:

Our problem is that we treat medical advances differently than we treat other technological advances…

In the early 80’s, the first personal computers cost over $10,000 a piece. Such computers were only purchased by people with the means to do so, and no one really questioned this inequality- for almost all new goods and services, it is only the upper income cohort that can afford to purchase them. This was true for personal computers in 1981 as it was true for automobiles in the early 20th century….In addition, one will surely find examples of luxury goods and services that never really spread down through the lower income cohorts because they were ultimately found to have no benefit or use-in other words, they were found to have no larger potential market.

However, when it comes to medical goods and services, especially goods and services that claim to be life-saving/prolonging, the inevitable inequality I wrote of above assaults our sense of fairness. We demand that such goods and services be available to all regardless of the cost and the efficacy. All other new goods and services first prove their worth to the small cohort that can afford the luxury of trying them out, but this is not the case with medical care- we consider it unfair that the wealthy can afford new cancer treatments of questionable worth- thus the process of real-world testing of efficacy is short-circuited. (Emphasis mine)

We seem to have the perverted thought that good health should have no price, and that all patients deserve the latest and greatest, when simply prescribing last year’s remedies (or even the old soap and water) would be significantly cheaper and create real improvement in the patient’s life, with only a tiny extra benefit from using the newest drug instead.

There’s also a good comment from “happyjuggler0″:

When Pharma comes out with a new drug treating something that was previously untreatable, it is meaningless to say that costs for that treatment have shot up, since there was no treatment for it before. Eventually, rather quickly I might add all things considered, this drug will go off patent and become dirt cheap. each year more and more drugs go off patent, and thus in reality drug costs are going down radically, not increasing.

From Maggie Mahar:

In the mid-ninties insurers were fairly successful at containing costs (if not improving care) for a few years–but the backlash was so great that they began losing customers. As a result, at the end of the nineties insurers decided to just cover whatever consumers asked for–and pass the cost along in the form of higher premiums. This explains why premiums have risen 87% in the past six years.
….
Why can’t consumers themselves push back–and demand lower prices and higher quality (as they do when shopping for other goods and services)? It’s not because they are, as Nathan puts it “you know, too lazy to actually talk to their doctor.” It’s because, first of all, they are sick….Secondly, even if they are not elderly, in pain or frigthened, the subject that they need to master is dauntingly complicated.
….
Moreover, the consumer is not in a position to push down prices because when you are dying of cancer (or congestive heart failure, etc.) you are not bargain-hunting. You become a “price-taker”–you will pay whatever price is necessary to end the pain, prolong life, be able to get up out of bed and function, etc.

Even if you are paying out of your own pocket you will do whatever is necessary to come up with the money–which is why medical bills are the leading cause of personal bankruptcy in this country.

One thing I don’t see, though, is why Maggie Mahar is lenient on insurance companies for being profit-driven, while blaming pharma companies on being profit-driven (in her comment, at least; I plan to read the book soon). She says, “After all, a for-profit corporation’s first reponsibility, by law, is to its shareholders–not to its customers,” but is far more reticent to give that excuse to drug companies: “Arguably, a for-profit manufactuer that promotes its product as widely as possible is only doing its job. (Though one would like to think “caveat emptor” shouldn’t have to apply when it comes to products that could mean the difference between life and death for the customer.)” Partly, it’s because it’s easy in this society to demonize pharmaceutical companies. It’s even possibly the fashion, right now. They do sometimes do unscrupulous things. But they don’t always, and there are plenty of people in their ranks that work hard at a very difficult task.

She also says,

For years, drug-makers and device-makers have fought tooth and nail against “head to head” comparisons that would test the effectiveness and safety of a new product against the older, less expensive product that it hopes to replace. And what’s amazing is that drug-makers and device-makers have won this battle: In order to earn FDA approval for a new product, the manufacturer only has to show that the benefits of his product outweighs the risks WHEN COMPARED TO A PLACEBO.

I really don’t see what’s wrong with comparing to placebos. The FDA is just supposed to be a gatekeeper screening for safety and efficacy. Why does everything have to be an improvement over what exists already? Knock-offs are good for consumers, too, because they increase competition and lower prices. How cheap would painkillers be if there was only one kind? Maybe cheap, maybe not, but because of competition, I can walk to a CVS and buy a 200 tablet bottle of ibuprofen (”Advil”) for $7.

Now, just because pharma makes the knock-off doesn’t mean doctors have to prescribe it. Of course, they need to know the data in order to decide what to prescribe. What is needed is an organization of researchers and doctors to do more head-to-head comparisons that would actually determine the efficacy of new drugs and determine standards of care, because doctors are really the gatekeepers of health care. I’m sure this already happens, to a certain extent, but it needs to happen more. Patients can’t negotiate the system, insurers are unwilling to, and do you really want pharma to stop producing drugs? Doctors are the ones prescribing and advising; that’s part of their job, so something should exist to help them. Now, if pharma and drug companies have been preventing head-to-head comparisons from happening at all, then fine, hound them for it. But I don’t think they are, since I’ve seen plenty of them appear in the wild.

Read the whole thread, if you have time; it’s very good, and Maggie Mahar makes some very good points, not all of which I agree with.

There’s a really controversial NEJM opinion article from Dr. Douglas Hanto on organ donor solicitation. He shows up to defend his position and convince skeptics on Paul Levy’s blog (the CEO of Beth Israel Deaconess Medical Center in Boston; isn’t the internet wonderful?). NextGen (shameless plug) offers free online access to the NEJM article.

Dr. Hanto advocates forbidding direct organ solicitation from patients to potential organ donors, arguing that it circumvents the fair distribution of organs based on medical need. I infer, though I’m not entirely clear on this, that he also advocates forbidding organ donation except to the central repository or list system that hospitals use to triage out the organs to patients. I will assume he advocates this position, since from the article, he seems to say this.

I really must respectfully disagree with Dr. Hanto. He states that organ donation must occur in this centrally managed way, because allowing organ donors to choose to whom they would like to donate would violate the “rights” of patients on the list. I’m not really sure which right he means, but he says, “Donor autonomy is not absolute and must consider the fair rights of others.” I’m not really sure this is a valid thing to say. What “rights” to other people have on organs or property of another? Is it just to say that the poor have a “right” to the private money donations of a wealthy individual? I think not. It is a private donation, and one freely given by one individual to another.

To put it another way, is it “fair” that Michael Jordan has so much money? People pay him tons of money to play basketball (well, they did in the past). Is it really good for society and fair for all that someone who plays basketball is making tons more money than, say, a hot-shot surgeon who saves people’s lives every day? Should we make it illegal for them to just give him money, and instead have the government pay each person what they “have a right to”? That’s pretty much complete communism, and I’m quite against that. People can do with their property what they will, wasteful or not. I assume that people have a right to do with their bodies as they will, wasteful or not. There’s no magical “fairness” right that gives other people rights to someone’s private property. That’s what makes it private. People’s bodies are part of their private property.

Dr. Hanto argues that there isn’t such a thing as complete donor autonomy, because organ transplantation surgery does require a significant commitment of resources and time that is not funded by the donor. That’s true, but it is true of any donation process, money, organs, blood, anything. The hospital is perfectly allowed to refuse to operate unless the donor donates to the central hospital list, but if a surgery team and hospital is willing, then it shouldn’t be illegal. Alternatively, some other donor or the patient or even the organ donor could cover the cost of doing the surgery, in compensation for taking up the hospital’s time and resources. If the patient is willing to pay the hospital to do this, the hospital is willing to take the money in compensation for their time, and the donor is willing to give the organ in this circumstance, there is nothing wrong with allowing the surgery to proceed.

Don’t get me wrong; it would probably be more kind for people to donate to the central bank, but I’m not giving out karma points or heaven points or whatever. These people have the right to do what they want. We are a society based on individual rights. We shouldn’t turn into a society where the government controls everything that people do.

Update: On the other hand, the US Government is doing nothing to help with the organ shortages. Here’s a good Freakonomics blog article on the (lack of an) organ market. And another one with links.

One particularly interesting and tragic side effect of preventing organ donation between specific groups of strangers would be that it would derail a whole slough of programs that are set to encourage people to donate organs, from LifeSharers, a group dedicated to donating organs but also who preferentially donates organs to those who vow to donate, and the New England Program for Kidney Exchange, which matches donor-recipient pairs, where (for example) one family member is willing to donate to another, but can’t due to blood-type incompatibility. They would be matched with another biologically complementary donor-acceptor pair in order to ensure that both patients get their organs.

A blog on this topic is the Organomics blog. One good entry is on arguments against the “coercion of the poor” objection to organ markets. I don’t always agree with the tone of the blog, or some of the ad hominem attacks it makes on critics of its ideas, but the ideas it has are (mostly) good one.

California is sending in their second wave of money into funding human embryonic stem cell (hESC) research, which is wonderful.

One of the problems I’ve heard from researchers, however, is that because all of the grants are publicized, they are fearful for their safety from religious terrorist groups, such as Christian terrorists, who might target their labs. When I visited Stanford, a new professor that I talked to had been part of a group of labs that were funded by the California stem cell initiative. She talked about how there were warnings going around that researchers shouldn’t be in the lab alone, to have labmates with them at all times, to carefully lock all doors, be aware of wandering strangers, and so on. It’s one thing that I just didn’t really consider with regards to research.

Of course, the ban on using federal money for any hESC research other than on the federally approved lines of cells also creates several problems, the obvious one being that this limits the flexibility of research, since we will have a hard time deciding whether our data about stem cells is just an eccentricity of the federal cell lines (which have some contamination or other problems) or whether they are real phenomena.

Another side effect that I hadn’t considered, however, is that nothing funded by federal money can be used, at all, for research on cell lines acquired through private funding. What this means is that even if you developed the stem cell line with private funding and have private funding grants for your continuing research, you can’t hire researchers with NIH or NSF money, you can’t use lab equipment that was bought by NIH/NSF money. You can’t even work in a building that was built partially with NIH/NSF money, which rules out almost all biomedical research buildings in the United States, apart from Janelia Farm (the Howard Hughes Medical Institute’s new research campus), biotech/pharma companies, and buildings like the new Harvard Stem Cell Institute. Thus, for all but the wealthiest of universities like Stanford or Harvard, embryonic stem cell research funded by private means becomes nearly impossible. Imagine having to built a whole new biomedical research facility, including labs, NMR facilities, mass spec facilities, and so on. That can easily run into the hundreds of millions of dollars to do, and most universities will probably decide that it’s just not worth it. Thus, even though Doug Melton has developed 17 new stem cell lines with private money and is willing to share them, no one can use them unless they have built new buildings and hired new people with private money.

Ahh, the burden of private research. Clearly, scientists have to do a better job of convincing the public that such research is ethical and necessary for the betterment of mankind.