Category: health care

Does Lithium Slow ALS?

Seth Roberts10 Comments

In 2008, an article in Proceedings of the National Academy of Sciences (PNAS) reported that lithium had slowed the progression of amyotrophic lateral sclerosis (ALS), which is always fatal. This article describes several attempts to confirm that effect of lithium. Three studies were launched by med school professors. In addition, patients at PatientsLikeMe also organized a test.

One of Nassim Taleb’s complaints about finance professors is their use of VAR (value at risk)Â to measure the riskiness of investments. It’s still being taught at business schools, he says. VAR assumes that fluctuations have a certain distribution. The distributions actually assumed turned out to grossly underestimate risk. VAR has helped many finance professionals take risks they shouldn’t have taken. It would have been wise for finance professors to wonder how well VAR does in practice, thereby to judge the plausibility of the assumed distribution. This might seem obvious. Likewise, the response to the PNAS paper revealed two problems that might seem obvious:

1. Unthinking focus on placebo controls. It would have been progress to find anything that slows ALS. Anything includes placebos. Placebos vary. From the standpoint of those with ALS, it would have been better to compare lithium to nothing than to some sort of placebo. As far as I can tell from the article, no med school professor realized this. No doubt someone has said that the world can be divided into people focused on process (on doing things a certain “right” way) and those focused on results (on outcomes). It should horrify all of us that med school professors appear focused on process.

2. Use of standard statistics (e.g., mean) to measure drug effects. I have not seen the ALS studies, but if they are like all other clinical trials I’ve seen, they tested for an effect by comparing means using a parametric test (e.g., a t test). However, effects of treatment are unlikely to have normal distributions nor are likely to be the same for each person. The usual tests are most sensitive when each member of the treatment group improves the same amount and the underlying variation is normally distributed. If 95% of the treatment group is unaffected and 5% show improvement, for example, the usual tests wouldn’t do the best job of noticing this. If medicine A helps 5% of patients, that’s an important improvement over 0%, especially with a fatal disease. And if you take it and it doesn’t help, you stop taking it and look elsewhere. So it would be a good idea to find drugs that only help a fraction of patients, perhaps a small fraction. The usual analyses may have caused drugs that help a small fraction of patients to be considered worthless when they could have been detected.

All the tests of lithium, including the PatientsLikeMe test, turned out negative. The PatientsLikeMe trial didn’t worry about placebo effects, so my point #1 isn’t a problem. However, my point #2 probably applies to all four trials.

Thanks to JR Minkel and Melissa Francis.

The Oncogene Theory of Cancer

Seth Roberts8 Comments

I am looking forward to reading Wrong: Why Experts Keep Failing Us — And How to Know When Not to Trust Them by David Freedman because of this sentence in an excerpt:

Cancer experts shake their heads today over the ways in which generations of predecessors wasted decades hunting down the mythical environmental or viral roots of most cancers, before pronouncing as a sure thing the more recent theory [that] cancer is caused by mutations in a small number of genes — a theory that, as we’ll see, has yielded almost no benefits to patients after two decades.

He’s referring to the oncogene theory of cancer, for which Michael Bishop and Harold Varmus won a Nobel Prize in 1989. I made a similar comment at a dinner:

Several years ago, at a big Thanksgiving dinner in an Oakland loft, I told the woman sitting next to me, a genetic counselor, what a travesty the Biology [Nobel] prizes were. The discovery that smoking causes lung cancer had improved the lives of millions of people, I said [yet the discoverers hadn’t gotten a Nobel Prize]; the discovery of so-called oncogenes hadn’t improved the life of even one person. She replied that she was the sister of [Harold Varmus]. The next day I learned she complained I had been rude!

I’m glad Freedman agrees with me. My low opinion of oncogene theory didn’t prevent Varmus from becoming head of the National Institutes of Health, whose recent budget was about $30 billion/year.

Thanks to Kathy Tucker.

What Antidepressants Do

Seth Roberts28 Comments

After I complained about lack of outrage in Daniel Carlat’s Unhinged, Bruce Charlton pointed me to this essay (registration required) by Simon Sobo, a psychiatrist. Sobo says something I may end up repeating every time the subject of antidepressants comes up:

Rat pups that are isolated from their mother and littermates produce ultrasonic sounds that are indicative of stress. SSRIs [the most popular type of antidepressants] reduce these sounds (Oliver, 1994). Is a chemical imbalance being corrected? I doubt it.

That’s a nice summing-up. Prozac (an SSRI) really does something, but the notion that it returns to normal something broken is absurd. Sobo also gives an example of how the anti-anxiety effect of such drugs works in practice:

Mrs. L. had originally required 40 mg of Paxil (paroxetine) per day to recover from a postpartum depression. After 12 months on the medication, an incident happened that disturbed her. During her lunchtime, she was visiting her 1-year-old son at his day care center when one of the workers began screaming at another infant instead of picking her up. The next day Mrs. L. went shopping during her lunch break. Later that week a co-worker became tearful during the course of a conversation with Mrs. L. regarding her own child’s day care center. Only then did Mrs. L. wonder about her decision to go shopping the day after she had witnessed the day care worker’s inappropriate reaction. She wondered if her Paxil had made her indifferent when ordinarily she would have reacted and worried about such a thing.

My research about mood suggests that depression is due to defective entrainment of a mood oscillator. It’s caused by something missing from the environment. “Chemical imbalance” has nothing to do with it.


Unhinged by Daniel Carlat

Seth Roberts7 Comments

Daniel Carlat, a Massachusetts psychiatrist, is the author of the excellent blog The Carlat Psychiatry Blog. He also wrote an excellent article in the New York Times Magazine about working on the side as a drug rep: He told other psychiatrists about new drugs. He quit (or was fired) because telling the truth wasn’t compatible with the job.

Unhinged, his new book (sent to me by the publisher after I asked for it twice — that’s how much I wanted to read it), covers the same ground. Its subtitle (or two subtitles) is/are The Trouble With Psychiatry — A Doctor’s Revelations about a Profession in Crisis. The contents were well-written, but none of it was new to me: the “chemical imbalance” theory of depression is a convenient myth, how drug reps work, how drug companies influence doctors, diagnosis difficulties, the cases of Charles Nemeroff and the like. (I did learn that Nemeroff was called “the boss of bosses” because of his prominence and power.) If any of his criticisms are new to you, this book is a great introduction. He uses many stories of patients to make his points.

Overall, I found the book too calm. What Nemeroff and others like him did I find outrageous but Carlat doesn’t sound outraged. Maybe he is, I have no idea, but his book is more reasonable-sounding than scornful and I would have preferred scornful. At one point he says he wrote an “angry” op-ed for the New York Times about something and I thought: good, some emotion!Â

The crisis of the subtitle (“A profession in crisis”) is enticing but is not borne out by the contents. Carlat dislikes aspects X, Y, and Z of his profession, but one person’s dissatisfaction does not equal crisis. I saw no signs he is part of a growing movement. My take on the trouble with psychiatry is that psychiatrists don’t understand what is wrong in almost every case they see and, due to lack of understanding, do a poor job of fixing the problem. Lack of understanding by doctors is nothing new and, until someone has a better understanding, doesn’t pose a professional problem. This basic truth goes unmentioned in Unhinged.

The David Healy Affair

Seth Roberts3 Comments

Bruce Charlton pointed me to this website full of information about how the University of Toronto rescinded a job offer to David Healy, a British psychiatrist, after he made negative comments about Prozac. Psychiatrists at the University of Toronto got a lot of money from Lilly, the maker of Prozac. Here’s something from a CBC documentary about it:

Although he refuses to interviewed, Dr. Nemeroff said through his lawyer that the [University of Toronto psychiatry] center asked for his opinion of Dr. Healy that day and he gave it. . . . Later that day he flew to New York where we do know he told a meeting of the American Foundation for Suicide Prevention exactly what he thought about Healy. One scientist who was there said Nemeroff’s attack was furious, angry, exercised, that the thrust was Healy was a nut.

If Charles Nemeroff calls you a nut . . .

Assorted Links

Seth Roberts2 Comments

The Costs and Benefits of Overtreatment

Seth Roberts5 Comments

This excellent NY Times Magazine article by Katy Butler describes the awful price paid by the Butler family when her father was given a pacemaker that kept him alive too long. The hospital, surgeon, and pacemaker manufacturer benefited by thousands of dollars. Her father was too out-of-it to make decisions about his health. His wife, who made the decision, was given too little information (not told of a much better alternative, not warned of the eventual outcome, which was likely) and, Butler seems to say, decided too fast. The pacemaker was implanted so that he could have a hernia operation — the hernia surgeon wouldn’t operate without it.

Butler’s article is excellent because it is personal, moving, and sheds light on a big issue that I rarely read about: the way “informed consent,” in practice, favors overtreatment. The patient or their representative makes the final decision, yes, but in most cases their decision is based mainly on information they’ve been given by their doctor or hospital, who benefit from one decision (yes, do something) but not the other (no).

The incentives for overtreatment continue, said Dr. Ted Epperly, the board chairman of the American Academy of Family Physicians, because those who profit from them — specialists, hospitals, drug companies and the medical-device manufacturers — spend money lobbying Congress and the public to keep it that way. . . The profit margins that manufacturers earn on cardiac devices is close to 30 percent. Cardiac procedures and diagnostics generate about 20 percent of hospital revenues and 30 percent of profits.

I liked Butler’s article partly because I’d had a similar, much smaller experience. I’m still pissed that during a discussion with Dr. Eileen Consorti, a Berkeley surgeon, of the costs and benefits of surgery to fix a nearly-undetectable hernia, she said nothing about side effects other than death. There are other possible bad effects of general anesthesia, which the operation would have involved. I complained to her assistant about her incomplete description of the risks. She didn’t respond, other than to threaten legal action (for not removing criticism of her for something else, I suppose).

Of course doctors, hospitals, and so on benefit from treatment. For me, the problem arises when (a) the benefits to patients are slight (compared to the benefits to the doctor, etc.), zero, or unknown or (b) the costs to patients are not well described. In both of these cases — the Butler family’s and mine — both (a) and (b) were true. Condition (a) is overtreatment, but Condition (b) makes things worse. If you propose to do something to me that could have an awful outcome, and from which you benefit, I would like to be warned of the awful outcome.

Dept. of Amplification. My original mention of Consorti was about how I couldn’t find any studies supporting her recommendation of surgery. She had said such studies existed. When I couldn’t find them, she promised to find them for me, but, several years later, has yet to. In the meantime, a reader of this blog found a relevant study (thanks, Kirk). Its results support my decision not to have the surgery that Consorti recommended.

Robin Hanson on doctors. How could we be this wrong about medicine? Thanks to Peter Spero.

Bruce Charlton on the Trouble With RCTs

Seth Roberts8 Comments

In response to my post about the trouble with randomized controlled trials (RCTs), Bruce Charlton, the editor of Medical Hypotheses, wrote me:

The golden age of medical discovery came before the widespread usage of RCTs. This golden age was all but over by the end of the 1960s; since then the rate of progress has declined (see refs such as Horrobin, Le Fanu and Wurtman in https://www.hedweb.com/bgcharlton/funding.html).

The earliest big and influential RCT in psychiatry was in the mid 1960s, and it was – in retrospect – misleading wrt MAOIs due to too low a dosage. Now that RCTs are regarded as indispensible, medical research is captive to Big Pharma

https://www.guardian.co.uk/commentisfree/2009/aug/08/seroxat-pharmaceutical-birth-defect

Another area of medicine [in addition to obstetrics] that has made big progress without being RCT-led is anesthetics. Dentistry is a third. These specialties are instead technology-led.

He also pointed me to an article by David Horrobin, the founder of Medical Hypotheses, titled “Are large clinical trials in rapidly lethal diseases usually unethical?” His answer was that some of their aspects are unethical: Prospective subjects (sick persons) are not told the low chance of benefit, the high chance of bad side effects, and the great financial benefit of such trials to the institutions that run them.

Horrobin’s article also made the point I made: The emphasis on RCTs suppresses innovation because only big well-established companies can afford them:

50 years ago, good scientific evidence of a potential therapeutic effect would quickly have generated a small clinical trial in one or two centers with perhaps 30 or 40 patients. Such a trial would have cost almost nothing. It would certainly have missed small or marginal effects, but it would not have missed the sort of large effect that most patients want. Unfortunately, now, such an approach has become impossible. . . . The escalation of costs has therefore drastically reduced the range of compounds from which new treatments can be drawn.

My reading of history is that suppression of innovation can last a long time but eventually change comes from the outside and the system collapses. Detroit, for example, has collapsed. General Motors was once as dominant as big drug companies are now.

The Dreams of Geneticists

Seth Roberts32 Comments

In a wiser world, we would see genetics research as we see astronomy: worth supporting, but without expecting practical benefit. In this world, however, genetics research is far better funded than astronomy and is expected to have practical benefits.

Unfortunately, the benefits have been slight. A New York Times article by Nicholas Wade makes this clear:

The primary goal of the $3 billion Human Genome Project — to ferret out the genetic roots of common diseases like cancer and Alzheimer’s and then generate treatments — remains largely elusive. Indeed, after 10 years of effort, geneticists are almost back to square one in knowing where to look for the roots of common disease.

“Largely” elusive? Completely elusive is more accurate, as far as I know. Not one treatment has come from this work.

In spite of ten years of failure, geneticists appear no wiser than before:

With most diseases, the common variants have turned out to explain just a fraction of the genetic risk. It now seems more likely [to prominent geneticists] that each common disease is mostly caused by large numbers of rare variants.

I know of no examples where a common (or any) disease has been shown to be caused by “large numbers of rare variants.” Perhaps these estimates of “genetic risk” are as misleading as asking what percentage of the area of a rectangle is determined by its width.

History repeats. Ten years ago, geneticists had zero examples of how mapping the human genome would help anyone with a common disease. Absence of any examples didn’t prevent such vast claims as human genome mapping will ““revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases”. From zero, they extrapolated to “most”.

It’s a sad comment on science journalism that, at the time, no one pointed out the absence of examples, as far as I know, and a sad comment on Wade, holder of a powerful and prestigious job, that he has not pointed it out now. He simply repeats a claim. At least he has noticed a gigantic failure after it happens, even if he inaccurately describes it (“largely” rather than “completely”).

Lack of examples of the practical value of genetic mapping didn’t keep a huge amount of money from being spent.

With the catalog [of common genetic variants] in hand, the second stage was to see if any of the variants were more common in the patients with a given disease than in healthy people. These studies required large numbers of patients and cost several million dollars apiece. Nearly 400 of them had been completed by 2009.

Ten failures would have been plenty; 400 failures shows the resistant-to-evidence nature of the whole enterprise. It’s an example of how a little biochemical-mechanism research goes a long way; a lot of biochemical-mechanism research goes a little way.

For geneticists, to acknowledge the lack of examples is scary. Their funding might be cut! So they don’t. But nothing prevents journalists from thinking for themselves and asking a supposedly “tough” question (“what’s an example?”) — although asking for examples is the most basic question there is.

Thanks to Alex Chernavsky. More about the cargo-cult nature of modern biology. If you don’t believe me, read this: “Of the roughly 50 companies at the conference, not one is focused on approaches related to tracking down new genes. . . . The one corner of the genome-focused biotech industry that’s thriving is the one churning out equipment and services to support researchers in their endless hunt for gene links.”

“Goes Against Everything I was Taught in Med School”

Seth Roberts5 Comments

A reader of this blog reported the following conversation with his doctor:

us: We want to put our autistic daughter on a gluten-free, casein-free diet. We have heard that some autistic kids have gotten some benefit from it.

Dr: It’s not something I know about, but there is no harm in it so feel free to give it a try. You know, I had a patient whose parents put her on a ketogenic diet to treat her seizures, and it seemed to help. That goes against everything I was taught in med school, but if it works, I think that’s great.

What’s telling here is the word everything. In medical school, the doctor seems to say, he was taught in a dozen ways that the sun revolves around the earth (or its health-science equivalent). If the alternative — the earth revolves around the sun — explains more of the data, well, “that’s great.” Again, it sounds like 1984: Part of the doctor’s brain has been turned off by repetition of something that supports the status quo.