Missing Data in Clinical Trials: FDA Officials Refuse to Set Limits

People who believe in “evidence-based medicine” say that double-blind clinical trials are the best form of evidence. Generally this is said by people who know very little about double-blind clinical trials. One reason they are not always the best form of evidence is that data may be missing. Nowadays more data is missing than in the past:

By [missing data] he [Thomas Marciniak] means participants who withdrew their consent to continue participating in the trial or went “missing” from the dataset and were not followed up to see what happened to them. Marciniak says that this has been getting worse in his 13 years as an FDA drug reviewer and is something that he has repeatedly clashed with his bosses about.

“They [his bosses] appear to believe that they can ignore missing and bad data, not mention them in the labels, and interpret the results just as if there was no missing or bad data,” he says, adding: “I have repeatedly asked them how much missing or bad data would lead them to distrust the results and they have consistently refused to answer that question.”

In one FDA presentation, he charted an increase in missing data in trials set up to measure cardiovascular outcomes.

“I actually plotted out what the missing data rates were in the various trials from 2001 on,” he adds. “It’s virtually an exponential curve.”

Another sort of missing data involves what is measured. In one study of whether a certain drug (losartan) increased cancer, lung cancer wasn’t counted as cancer. In another case, involving Avandia, a diabetes drug, “serious heart problems . . . were not counted in the study’s tally of adverse events.”

Here is a presentation by Marciniak. At one point, he asks the audience, Why should you believe me rather than the drug company (GSK)? His answer: “Neither my job nor (for me) $100,000,000’s are riding on the results.” It’s horrible, but true: Our health care system is almost entirely run by people who make more money (or make the same amount of money for less work) if they exaggerate its value — if they ignore missing data and bad side effects, for example. Why the rest of us put up with this in the face of overwhelming evidence of exaggeration (for example, tonsillectomies) is an interesting question.

Thanks to Alex Chernavsky.

Assorted Links

  • Interview with sufferer from mercury amalgam fillings. Stephen Barrett, founder of Quackwatch, says mercury amalgam fillings are perfectly safe. For many people, this might be true. It is not always true.
  • “She was given a three to five year sentence.” One of the greatest wrist-slaps of all time. She deserves at least one year in jail per falsification, which would be several thousand years in jail.
  • Ron Unz, the minimum wage and social innovation
  • Dairy consumption and heart disease risk. “The majority of observational studies have failed to find an association between the intake of dairy products and increased risk of CVD, coronary heart disease, and stroke, regardless of milk fat levels.”
  • Tourism and mental illness. “A Canadian woman was denied entry to the United States last month because she had been hospitalized for depression in 2012. Ellen Richardson could not visit, she was told, unless she obtained “medical clearance” from one of three Toronto doctors approved by the Department of Homeland Security.” Horrifying.
  • Snorting baby shampoo to cure sinusitis. A good example of personal science. His understanding of biofilms led him to try baby shampoo. It is also interesting that he doesn’t try to strengthen his immune system to solve the problem or maybe he doesn’t know how to. A professional sinusitis researcher would never discover what he did, yet another example of how our healthcare system ignores cheap treatments.

Thanks to Allen Jackson and Phil Alexander.

Dark Picture of Doctors

A New York Times article about error in a risk calculator paints an unflattering picture of doctors:

1. The risk calculator supposedly tells you your risk of a heart attack, to help you decide if you should take statins. It overestimates risk by about 100%. The doctors in charge of it were told about the error a year ago. They failed to fix the problem.

2. The doctors in charge of the risk calculator are having trouble figuring out how to respond. The possibility of a simple retraction seems to not have occurred to them. As one commenter said, “That the researchers, once confronted with the evidence it was faulty, struggled with how to handle the issue is quite telling.”

3. In the comments, a retired doctor thinks the problem of causation of heart disease is very simple:

Statins . . . are only one component in the prevention and treatment of coronary artery disease. Item number one is to have a normal weight. Item two is never smoke. Item three is exercise. Four is to eat an intelligent diet. Five is to remove stress from your life as much as practical. If everybody did these five things (all of which are free), the incidence of coronary artery disease would plummet and many fewer would need statins.

This reminds me of a doctor who told me she knew why people are fat: They eat too much and exercise too little. She was sure.

4. In the comments, a former medical writer writes:

Several years ago, I wrote up, as internal reports, about two dozen transcripts recorded at meetings with local doctors that a major drug company held all around the country. The meetings concerned its statin. Two ideas presented at these meetings by the marketing team, and agreed with by the physician attendees, were: 1) the muscle pain reported by patients was almost never caused by the statin but was the result of excessive gardening, golfing, etc; 2) many children should be prescribed a statin and told that they would have to take the drug for life.

5. Another doctor, in the comments, says something perfectly reasonable, but even her comment makes doctors look bad:

I am a physician and I took statins for 2 years. Within the first 6 months, I developed five new serious medical problems, resulting in thousands of dollars spent on treatments, diagnostic tests, more prescription medications, and lost work. Neither I nor any of my 6 or 7 different specialists thought to suspect the statin as the source of my problems. I finally figured it out on my own. It took 3 more years for me to get back to my baseline state of health. I had been poisoned. I see this all the time now in my practice of dermatology. Elderly patients are on statins and feel lousy, some of whom are also on Alzheimer’s drugs, antidepressants, Neurontin for chronic pain, steroids for fibromyalgia. These poor people have their symptoms written off as “getting older” by their primary physicians, most of whom I imagine are harried but well intentioned, trying to follow guidelines such as these, and so focused on treating the numbers that they fail to see the person sitting in front of them. The new guidelines, with their de-emphasis on cholesterol targets, seem to tacitly acknowledge that cholesterol lowering has little to do with the beneficial actions of statins. The cholesterol hypothesis is dying. If statins “work” by exerting anti-inflammatory benefits, then perhaps we should seek safer alternative ways to accomplish this, without subjecting patients to metabolic derangement.

6. A patient:

My previous doctor saw an ultrasound of my Carotid Artery with a very small buildup and told me I needed to take crestor to make it go away. That was four years ago and I still suffer from some memory loss episodes as a result. The experience was terrible and he’s toast because he denied it could happen.

7. A bystander:

For the past couple of years my job has involved working with academic physicians at a major medical school. After watching them in action — more concerned with personal reputation, funding and internecine politics than with patients — it’s a wonder any of us are limping along. And their Mickey Mouse labs and admin organizations can barely organize the annual staff holiday potluck without confusion and strife. So these botched-up results don’t surprise me at all.

I am not leaving out stuff that makes doctors look good. Maybe this is a biassed picture, maybe not. What I find curious is the wide range of bad behavior. I cannot explain it. Marty Makary argued that doctors behave badly due to lack of accountability but that doesn’t easily explain ignoring a big error when pointed out (#1), an immature response (#2), a simplistic view of heart disease (#3), extraordinary callousness (#4) and so on.  In her last book (Dark Age Ahead), Jane Jacobs wrote about failure of learned professions (such as doctors) to police themselves. Again, however, I don’t see why better policing would improve the situation.

Thanks to Alex Chernavsky.

Modern Cargo Cult Science: Evidence-Based Medicine, Science Fiction in China

In a graduation speech, Richard Feynman called certain intellectual endeavors “cargo cult science,” meaning they had the trappings of science but not the substance. One thing he criticized was rat psychology. He was wrong about that. Sure, as Feynman complained, lots of rat psychology experiments have led nowhere, just as lots of books aren’t good. But you need to publish lots of bad books to support the infrastructure necessary to publish a few good ones. The same is true of rat psychology experiments. A few are very good. The bad make possible the good. Rat psychology experiments, especially those by Israel Ramirez and Anthony Sclafani, led me to a new theory of weight control, which led me to the Shangri-La Diet.

Cargo cult science does exist.  The most important modern example is evidence-based medicine. Notice how ritualistic it is and how little progress medicine has made since it became popular. An evidence-based medicine review of tonsillectomies failed to realize they were worse than voodoo. Voodoo, unlike a tonsillectomy, does not damage your immune system. The evidence-based medicine reviewers appeared not to know that tonsils are part of the immune system. Year after year, the Nobel Prize in Medicine or Physiology tells the world, between the lines of the press release, that once again medical researchers have failed to make progress on any major disease, as the prize is always given for work with little or no practical value. In the 1950s, the polio vaccine was progress; so was figuring out that smoking causes lung cancer (which didn’t get a Nobel Prize). There have been no comparable advances since then. Researchers at top medical schools remain profoundly unaware of what causes heart disease, most cancers, depression, bipolar disorder, obesity, diabetes and so on.

I came across cargo-cult thinking recently in a talk by Neil Gaiman:

I was in China in 2007, at the first party-approved science fiction and fantasy convention in Chinese history. And at one point I took a top official aside and asked him Why? SF had been disapproved of for a long time. What had changed?

It’s simple, he told me. The Chinese were brilliant at making things if other people brought them the plans. But they did not innovate and they did not invent. They did not imagine. So they sent a delegation to the US, to Apple, to Microsoft, to Google, and they asked the people there who were inventing the future about themselves. And they found that all of them had read science fiction when they were boys or girls.

I know about Chinese engineers at Microsoft and Google in Beijing. They want to leave the country. An American friend, who worked at Microsoft, was surprised by the unanimity of their desire to leave. I wasn’t surprised. Why innovate or invent if the government might seize your company? Which is the main point of Why Nations Fail. Allowing science fiction in China doesn’t change that.

Thanks to Claire Hsu.

Assorted Links

Thanks to Sean Curley and Alex Chernavsky.

Meat as Health Food, Food Preference as Wisdom

A Chinese friend of mine had a cold. After a few weeks, she was still sick.  I suggested she eat meat — it would provide the amino acids needed to make antibodies. She did want to eat meat, she said, but her mom thought that meat was bad for a sick person — an idea from Traditional Chinese Medicine, I guess.

Yesterday I had a desire to eat meat. That was odd; I didn’t usually feel that way. I ate all the meat in the refrigerator (slices of cured meat) but it wasn’t much. I ate three eggs. That, too, was odd — usually one egg is plenty. In the evening, I distinctly wanted more meat but decided against going out to get some. This morning I woke up with the flu. I could tell by the joint pain. So that’s what joint pain is, I thought. I’d read about flu and written about it, but, before this morning, cannot remember having it.  How is the flu different from a cold? I once tried to find out. I might not have come down with today’s case of the flu were it not for two events: yesterday’s decision not to eat meat; and, the day before, running into a friend who had just left the house after being home-bound for four days with the flu. He shook my hand twice.

Humans (including me) are exceedingly gullible; my evolutionary explanation is that this makes us easier to lead. Gullibility — we believe something just because an authority says it — is cement. It keeps members of a group together. Better that 10 people do one thing (e.g., live in one place) than ten things, in many cases. Pointless to waste time on unresolvable and divisive arguments. Doctors, both Western and Eastern, take advantage of our gullibility. As my friend says, “doctors hurt you” because they tell you to do something different from what you want to do (e.g., eat meat). What you want to do is actual wisdom. We’ve been shaped by evolution to want to do what is good for us and what we want to eat is a giant clue to what we should eat. In nutrition research, this line of thinking, which is called dietary self-selection research, is nearly moribund, in spite of we need to eat fermented foods to be healthy. Fermented foods, much more than other foods, satisfy our desire for sour, umami-flavored and complex-flavored foods. For example, it is easy to produce complexity via fermentation; it is hard to produce it in other ways.

As for my flu, I went to the store and got pork and duck. By evening I felt much better.


Back Pain Cured by Sarno’s Ideas

Two years ago, a professor of decision science wrote me to say that Vitamin D3 in the morning greatly improved his sleep. Recently he wrote again:

Once again you have dramatically improved my life through your blog.

In this Assorted Links post you offered:

The back pain of a friend of mine, which had lasted 20 years and was getting worse, went away when he followed this doctor’s advice

I read the link about Dr. Sarno and went to Amazon to check out his book, “Healing Back Pain”. 700 reviews with a 4.5 star rating. I spent two hours reading the reviews. Person after person saying, “my back is better” and nobody really described what the book had them do. I bought it two weeks ago.

In a nutshell, Sarno says that this type of back pain is caused by oxygen deprivation of some back muscles/tendons, and that the mind has does this as a defense mechanism so I don’t have to confront my subconscious anger.

I don’t have to pinpoint the source of my anger. I don’t have to come to grips with it and stop being angry. I just have to acknowledge the anger. That’s it. I read half the book in one sitting. I thought, this is crazy, but it has 700 4+ stars at Amazon. Maybe it does work.

My wife and I have two cars. One of them is a small Saturn. I hate it. It hurts my back to get in or out of it, and if I drive for more than five minutes I have to squirm to keep the back pain under control. Last week I took the Saturn for two half hour drives with only one wince of pain. Today I took it to the gym (a five minute drive) but it didn’t hurt to get in or out.

In the morning, to get out of bed, I have to roll over and swing my legs out toward the floor and then prop myself up into a sitting position. At least, that’s how I’ve done it for the past year. This week, I just sat up in bed with no pain. Every morning.

I am still a bit weak in the lower back, after more than a year of restricted physical activity. But this is amazing.

Interview with Sarno on Larry King Live (1999).

Saturated Fat and Heart Attacks

After I discovered that butter made me faster at arithmetic, I started eating half a stick (66 g) of butter per day. After a talk about it, a cardiologist in the audience said I was killing myself. I said that the evidence that butter improved my brain function was much clearer than the evidence that butter causes heart disease. The cardiologist couldn’t debate this; he seemed to have no idea of the evidence.

Shortly before I discovered the butter/arithmetic connection, I had a heart scan (a tomographic x-ray) from which is computed an Agaston score, a measure of calcification of your blood vessels. The Agaston score is a good predictor of whether you will have a heart attack. The higher your score, the greater the probability. My score put me close to the median for my age. A year later — after eating lots of butter every day during that year — I got a second scan. Most people get about 25% worse each year.  My second scan showed regression (= improvement). It was 40% better (less) than expected (a 25% increase). A big increase in butter consumption was the only aspect of my diet that I consciously changed between Scan 1 and Scan 2.

The improvement I observed, however surprising, was consistent with a 2004 study that measured narrowing of the arteries as a function of diet. About 200 women were studied for three years. There were three main findings. 1. The more saturated fat, the less narrowing. Women in the highest quartile of saturated fat intake didn’t have, on average, any narrowing. 2. The more polyunsaturated fat, the more narrowing. 3. The more carbohydrate, the more narrowing. Of all the nutrients examined, only saturated fat clearly reduced narrowing. Exactly the opposite of what we’ve been told.

As this article explains, the original idea that fat causes heart disease came from Ancel Keys, who omitted most of the available data from his data set. When all the data were considered, there was no connection between fat intake and heart disease. There has never been convincing evidence that saturated fat causes heart disease, but somehow this hasn’t stopped the vast majority of doctors and nutrition experts from repeating what they’ve been told.

Assorted Links

Thanks to Alex Chernavsky.

Progress in Psychiatry and Psychotherapy: The Half-Full Glass

Here is an excellent introduction to cognitive-behavioral therapy (CBT) for depression, centering on a Stanford psychiatrist named David Burns. I was especially interested in this:

[Burns] currently draws from at least 15 schools of therapy, calling his methodology TEAM—for testing, empathy, agenda setting and methods. . . . Testing means requiring that patients complete a short mood survey before and after each therapy session. In Chicago, Burns asks how many of the therapists [in the audience] do this. Only three [out of 100] raise their hands. Then how can they know if their patients are making progress? Burns asks. How would they feel if their own doctors didn’t take their blood pressure during each check-up?

Burns says that in the 1970s at Penn [where he learned about CBT], “They didn’t measure because there was no expectation that there would be a significant change in a single session or even over a course of months.” Forty years later, it’s shocking that so little attention is paid to measuring whether therapy makes a difference. . . “Therapists falsely believe that their impression or gut instinct about what the patient is feeling is accurate,” says May [a Stanford-educated Bay Area psychiatrist], when in fact their accuracy is very low.

When I was a graduate student, I started measuring my acne. One day I told my dermatologist what I’d found. “Why did you do that?” he asked. He really didn’t know. Many years later, an influential psychiatrist — Burns, whose Feeling Good book, a popularization of CBT, has sold millions of copies — tells therapists to give patients a mood survey. That’s progress.

But it is also a testament to the backward thinking of doctors and therapists that Burns didn’t tell his audience:

–have patients fill out a mood survey every day
–graph the results

Even more advanced:

–use the mood scores to measure the effects of different treatments

Three cheap safe things. It is obvious they would help patients. Apparently Burns doesn’t do these things with his own patients, even though his own therapy (TEAM) stresses “testing” and “methods”. It’s 2013. Not only do psychiatrists and therapists not do these things, they don’t even think of doing them. I seem to be the first to suggest them.

Thanks to Alex Chernavsky.

What Goes Unsaid: Self-Serving Health Research

“The realization that the world is often quite different from what is presented in our leading newspapers and magazines is not an easy conclusion for most educated Americans to accept,” writes Ron Unz. He’s right. He provides several examples of the difference between reality and what we are told. In finance, there are Bernie Madoff and Enron. Huge frauds are supposed to be detected. In geopolitics, there is the Iraq War. Saddam Hussein’s Baathists and al-Quada were enemies. Invading Iraq because of 9/11 made as much sense as attacking “China in retaliation for Pearl Harbor” — a point rarely made before the war. In these cases, the national media wasn’t factually wrong.  No one said Madoff wasn’t running a Ponzi scheme. The problem is that something important wasn’t said. No one said Madoff was running a Ponzi scheme.

This is how the best journalists (e.g., at The New Yorker and the New York Times) get it wrong — so wrong that “best” may be the wrong word. In the case of health, what is omitted from the usual coverage has great consequences. Health journalists fail to point out the self-serving nature of health research, the way it helps researchers at the expense of the rest of us.

The recent Health issue of the New York Times Magazine has an example. An article by Peggy Orenstein about breast cancer, meant to be critical of current practice, goes on and on about how screening has not had the promised payoff. As has been widely noted. What Orenstein fails to understand is that the total emphasis on screening was a terrible mistake to begin with. Before screening was tried, it was hard to know whether it would fail or succeed; it was worth trying, absolutely. But it was always entirely possible that it would fail — as it has. A better research program would have split the funds 50/50 between screening and lifestyle-focused prevention research.

The United States has the highest breast cancer incidence (age-adjusted) rates in the world — about 120 per 100,000 women, in contrast to 20-30 per 100,000 women in poor countries. This implies that lifestyle changes can produce big improvements. Orenstein doesn’t say this. She fails to ask why the Komen Foundation has totally emphasized cure (“race for the cure”) over prevention due to lifestyle change. In a long piece, here is all she says about lifestyle-focused prevention:

Many [scientists and advocates] brought up the meager funding for work on prevention. In February, for instance, a Congressional panel made up of advocates, scientists and government officials called for increasing the share of resources spent studying environmental links to breast cancer. They defined the term liberally to include behaviors like alcohol consumption, exposure to chemicals, radiation and socioeconomic disparities.

Nothing about how the “meager funding” was and is a huge mistake. Xeni Jardin of Boing Boing called Orenstein’s article “a hell of a piece“. Fran Visco, the president of the National Breast Cancer Coalition, praised Orenstein’s piece and wrote about preventing breast research via a vaccine. Jardin and Visco, like Orenstein, failed to see the elephant in the room.

Almost all breast-cancer research money has gone to medical school professors (most of whom are men). They don’t do lifestyle research, which is low-tech. They do high-tech cure research. Breast cancer screening, which is high-tech, agrees with their overall focus. High-tech research wins Nobel Prizes, low-tech research does not. For example, those who discovered that smoking causes lung cancer never got a Nobel Prize. Health journalists, most of whom are women, apparently fail to see and definitely fail to write how they (and all women) are harmed by this allocation of research effort. The allocation helps the careers of the researchers (medical school professors); it hurts anyone who might get breast cancer.

Eric Kandel Sheds Light On Who Wins Nobel Prizes

The most interesting thing about the Nobel Prize in Medicine is its predictable irrelevance to major health problems. Year after year, the prize-winning work has failed to reduce heart disease, cancer, depression, stroke, diabetes, schizophrenia, and so on. Another interesting thing about the Nobel Prize in Medicine is that Eric Kandel, a Columbia Medical School professor, managed to win one. In 1986, a book called Explorers of the Black Box: The Search for the Cellular Basis of Memory by Susan Allport told how Kandel tried to take credit for other people’s discoveries. Not a pretty picture. Yet in 2000 he won a Nobel Prize for those or very similar discoveries. Did Allport exaggerate? Did her sources deceive her? Did Kandel — contrary to what Allport’s book seems to say — deserve a Nobel Prize?

I can’t answer these questions. However, a recent article by Kandel (“A New Science of Mind”) in the New York Times sheds light on how well he understands medicine and neuroscience. Not well, it turns out. He writes:

We are nowhere near understanding [psychiatric disorders] as well as we understand disorders of the liver or the heart.

Actually, our understanding of liver and heart disorders is close to zero, matching our understanding of psychiatric disorders. If we had some understanding of heart disease, for example, we would know why heart disease is much rarer in Japan than in the United States. Continue reading “Eric Kandel Sheds Light On Who Wins Nobel Prizes”

“The Cause of Ulcers is Bacteria” Makes as Much Sense as “The Cause of Car Accidents is Cars”

If I were to look at you, and say, in a serious tone of voice, “The cause of car accidents is cars”, you’d think I’m nuts. It’s not a useful statement. Yet many medical and science experts — including the people who award the Nobel Prize in Physiology or Medicine — believe it is helpful to say “the cause of ulcers is bacteria”. The two statements are similar because only a small percentage of cars get in accidents and only a small percentage of people infected with H. pylori, the bacterium that supposedly “causes ulcers”, get ulcers. A helpful investigation of what causes ulcers would figure out the crucial difference(s) between those infected with H. pylori who don’t get ulcers (almost all) and those who do (very few).

I recently encountered the “the cause of ulcers is bacteria” twice in one day. Once in a book review by John Timpane:

Barry Marshall, who discovered what causes stomach ulcers, played fast, loose, and messy with his methods and data. He was right, and got the right answer, and now we know.

(Timpane is right about the “fast, loose, and messy” part. Marshall ingested a large number of H. pylori. He failed get an ulcer — and claimed the outcome supported his view that H. pylori causes ulcers.) And once in The New Yorker, in a long article about the benefits of microbes, especially H. pylori, by Michael Specter:

In 1982, to the astonishment of the medical world, two scientists, Barry Marshall and J. Robin Warren, discovered that H. pylori is the principal cause of gastritis and peptic ulcers.

Should I expect science journalists to understand causality? Maybe not. But it is interesting that the people who award the Nobel Prize in Medicine and “the medical world” do not understand it.

Stagnation in Psychiatry

A recent New York Times article lays it out:

Fully 1 in 5 Americans take at least one psychiatric medication. Yet when it comes to mental health, we are facing a crisis in drug innovation. . . . Even though 25 percent of Americans suffer from a diagnosable mental illness in any year, there are few signs of innovation from the major drug makers.

The author has no understanding of the stagnation, yet is opinionated:

The simple answer [to what is causing the stagnation] is that we don’t yet understand the fundamental cause of most psychiatric disorders [what does “fundamental cause” mean? — Seth], in part because the brain is uniquely difficult to study; you can’t just biopsy the brain and analyze it. That is why scientists have had great trouble identifying new targets for psychiatric drugs.

The great increase in depression has an environmental cause. Meaning that depressed brains (aside from the effects of depression) are the same as non-depressed brains. Someone who knows that would not talk about biopsying the brain.

You come to a room with a door. If you don’t know how a door works, you are going to do a lot of damage getting inside. That is modern psychiatry. I described a new explanation for depression in this article (see Example 2).

Thanks to Alex Chernavsky.

The Truth in Small Doses: Interview with Clifton Leaf (Part 2 of 2)

Part 1 of this interview about Leaf’s book The Truth in Small Doses: Why We’re Losing the War on Cancer — and How to Win It was posted yesterday.

SR You say we should “let scientists learn as they go”. For example, reduce the need for grant proposals to require tests of hypotheses. I agree. I think most scientists know very little about how to generate plausible ideas. If they were allowed to try to do this, as you propose, they would learn how to do it. However, I failed to find evidence in your book that a “let scientists learn as they go” strategy works better (leaving aside Burkitt). Did I miss something?

CL Honestly, I don’t think we know yet that such a strategy would work. What we have in the way of evidence is a historical control (to some extent, we did try this approach in pediatric cancers in the 1940s through the 1960s) and a comparator arm (the current system) that so far has been shown to be ineffective.

As I tried to show in the book, the process now isn’t working. And much of what doesn’t work is what we’ve added in the way of bad management. Start with a lengthy, arduous, grants applications process that squelches innovative ideas, that funds barely 10 percent of a highly trained corps of academic scientists and demoralizes the rest, and that rewards the same applicants (and types of proposals) over and over despite little success or accountability. This isn’t the natural state of science. We BUILT that. We created it through bad management and lousy systems.
Same for where we are in drug development. We’ve set up clinical trials rules that force developers to spend years ramping up expensive human studies to test for statistical significance, even when the vast majority of the time, the question being asked is of little clinical significance. The human cost of this is enormous, as so many have acknowledged.

With regard to basic research, one has only to talk to young researchers (and examine the funding data) to see how badly skewed the grants process has become. As difficult (and sometimes inhospitable) as science has always been, it has never been THIS hard for a young scientist to follow up on questions that he or she thinks are important. In 1980, more than 40 percent of major research grants went to investigators under 40; today it’s less than 10 percent. For anyone asking provocative, novel questions (those that the study section doesn’t “already know the answer to,” as the saying goes), the odds of funding are even worse.

So, while I can’t say for sure that an alternative system would be better, I believe that given the current state of affairs, taking a leap into the unknown might be worth it.

SR I came across nothing about how it was discovered that smoking causes lung cancer. Why not? I would have thought we can learn a lot from how this discovery was made.

CL I wish I had spent more time on smoking. I mention it a few times in the book. In discussing Hoffman (pg. 34, and footnote, pg. 317), I say:

He also found more evidence to support the connection of “chronic irritation” from smoking with the rise in cancers of the mouth and throat. “The relation of smoking to cancer of the buccal [oral] cavity,” he wrote, “is apparently so well established as not to admit of even a question of doubt.” (By 1931, he would draw an unequivocal link between smoking and lung cancer—a connection it would take the surgeon general an additional three decades to accept.)

And I make a few other brief allusions to smoking throughout the book. But you’re right, I gave this preventable scourge short shrift. Part of why I didn’t spend more time on smoking was that I felt its role in cancer was well known, and by now, well accepted. Another reason (though I won’t claim it’s an excusable one) is that Robert Weinberg did such a masterful job of talking about this discovery in “Racing to the Beginning of the Road,” which I consider to be the single best book on cancer.

I do talk about Weinberg’s book in my own, but I should have singled out his chapter on the discovery of this link (titled “Smoke and Mirrors”), which is as much a story of science as it is a story of scientific culture.

SR Overall you say little about epidemiology. You write about Burkitt but the value of his epidemiology is unclear. Epidemiology has found many times that there are big differences in cancer rates between different places (with different lifestyles). This suggests that something about lifestyle has a big effect on cancer rates. This seems to me a very useful clue about how to prevent cancer. Why do you say nothing about this line of research (lifestyle epidemiology)?

CL Seth, again, I agree. I don’t spend enough time discussing the role that good epidemiology can play in cancer prevention. In truth, I had an additional chapter on the subject, which began by discussing decades of epidemiological work linking the herbicide 2-4-D with various cancers, particularly with prostate cancer in the wheat-growing states of the American west (Montana, the Dakotas and Minnesota). I ended up cutting the chapter in an effort to make the book a bit shorter (and perhaps faster). But maybe that was a mistake.

For what’s it worth, I do believe that epidemiology is an extremely valuable tool for cancer prevention.

[End of Part 2 of 2]

The Truth in Small Doses: Interview with Clifton Leaf (Part 1 of 2)

I found a lot to like and agree with in The Truth in Small Doses: Why We’re Losing the War on Cancer — and How to Win It by Clifton Leaf, published recently. It grew out of a 2004 article in Fortune in which Leaf described poor results from cancer research and said that cancer researchers work under a system that “rewards academic achievement and publication over all else” — in particular, over “genuine breakthroughs.” I did not agree, however, with his recommendations for improvement, which seemed to reflect the same thinking that got us here. It reminded me of President Obama putting in charge of fixing the economy the people who messed it up. However, Leaf had spent a lot of time on the book, and obviously cared deeply, and had freedom of speech (he doesn’t have to worry about offending anyone, as far as I can tell) so I wondered how he would defend his point of view.

Here is Part 1 of an interview in which Leaf answered written questions. Continue readingThe Truth in Small Doses: Interview with Clifton Leaf (Part 1 of 2)”

Are Drug Companies Becoming Less Law-Abiding?

Alex Chernavsky drew my attention to a report of the giant fines assessed drug companies for fraudulent marketing. For example,

Merck agreed to pay a fine of $950 million related to the illegal promotion of the painkiller Vioxx, which was withdrawn from the market in 2004 after studies found the drug increased the risk of heart attacks. The company pled guilty to having promoted Vioxx as a treatment for rheumatoid arthritis before it had been approved for that use. The settlement also resolved allegations that Merck made false or misleading statements about the drug’s heart safety to increase sales.

Fines, of course, are supposed to reduce bad behavior. Here are the fines by year:

  • 2009: 2 fines
  • 2010: 1 fine
  • 2011: 1 fine
  • 2012: 5 fines

This pattern does not suggest the fines are working. Drug companies, of course, are very big. I would like to see cross-industry comparisons: which industries pay the most in fines per dollar of revenue?


Assorted Links

  • Open Source Malaria
  • Criticism of Malcolm Gladwell by The KoreanGladwell’s persuasive rebuttal, more from The Korean, more from Gladwell. I thought the work under discussion (“ethnic theory of plane crashes”) was the best part of Outliers. Gladwell summarizes it: “That chapter in Outliers is about a series of extraordinary steps taken by Korean Air, in which an institution on the brink of collapse and disgrace turned themselves into one of the best airlines in the world. They did so by bravely confronting the fact that a legacy of their cultural heritage was frustrating open communication in the cockpit. That is not a slight on Korean culture, or any other high-power distance culture for that matter.”
  • More praise for the new TV show Naked and Afraid on the Discovery Channel. It really is riveting.
  • Ziploc omelette. Poor man’s sous vide.

Thanks to Nicole Harkin.

How to Detect Dementia

Dementia is common. You might think that doctors and neuropsychologists would have a good understanding of how to detect it. Judging from a recent New York Times article, they don’t. The article is based on a study that found that people who report memory problems not detected by a standard test turn out to be more likely to end up with dementia (measured by a standard test) than those that don’t. This isn’t surprising; what’s more revealing is how people who report memory problems have been treated in the past: their complaints have been dismissed. For example:

Patients like this have long been called “the worried well,” said Creighton Phelps, acting chief of the dementias of aging branch of the National Institute on Aging. “People would complain, and we didn’t really think it was very valid to take that into account.”

Doctors had no idea whether these complaints were valid but rather than admit this ignorance they . . . confabulated. They claimed, based on nothing, that the complaints were not valid. It reminds me of a surgeon telling me that research supported her claim that I needed surgery (for a hard-to-notice hernia). No such research existed. When I asked her what research? she said she would find it. She was bluffing, in other words. That’s just one doctor making up evidence. Here it has been a whole group of doctors.

The problem isn’t just confabulation. Apparently doctors in this area fail to understand basic principles of measurement. When Patient Y visits Doctor X and complains of memory problems, Doctor X gives Patient Y a series of memory tests. Only if Patient Y scores below normal range does Doctor X think that Patient Y’s complaint is “real”. For example:

The man complained of memory problems but seemed perfectly normal. No specialist he visited detected any decline. “He insisted that things were changing, but he aced all of our tests,” said Rebecca Amariglio, a neuropsychologist at Brigham and Women’s Hospital in Boston. 

Amariglio apparently fails to understand that a series of measurements on one person — which is what the man’s complaint was based on, comparing himself now to himself in the past — is going to be vastly more sensitive to change than a comparison of one person to other people. A reasonable response to a complaint of memory loss would be: This is hard to detect with a one visit. Let’s give you a sensitive test and have you come back in six months to see if you decline more than normal. Judging from the Times article, doctors still haven’t figured this out.

Speaking of memory decline, Posit Science still hasn’t sent me the data they promised to send me.

Thanks to Alex Chernavsky.

Assorted Links

  • A hospital specialized for hernia surgery. Much better outcomes, much lower cost. The combination (better outcomes, favored by patients, and lower cost, favored by insurers) suggests this could spread, if patients plus insurers > doctors plus hospitals.
  • Unlocking umami. I use koji salt, works really well. Comes in plastic squeeze container, which says “today’s newest seasoning”.
  • David Grime’s 2012 article on the same subject It is more methodologically sophisticated but reaches the same conclusion: The rise and fall is not explained by any popular theory (e.g., smoking causes heart disease, cholesterol causes heart disease). Because of this failure, using those theories to try to prevent heart disease (e.g., telling people stop smoking) makes little sense. Likewise, I doubt that experts know why dementia is decreasing, although they have theories.
  • Hypochondriasis and self-tracking

Thanks to Alex Chernavsky.