The power of baselines

From today’s Guardian:


It took decades to establish that smoking causes lung cancer. Heavy smoking increases the risk of lung cancer by a factor of about 11, the largest risk ratio for any common risk factor for any disease. But that doesn’t make it peculiar that there should be any non-smokers with lung cancer.

As with my discussion of the horrified accounts of obesity someday overtaking smoking as a cause of cancer, the main cause is a change in the baseline level of smoking. As fewer people smoke, and as non-smokers stubbornly continue to age and die, the proportional mortality of non-smokers will inevitably increase.

It is perfectly reasonable to say we should consider diverting public-health resources from tobacco toward other causes of disease, as the fraction of disease caused by smoking declines. And it’s particularly of concern for physicians, who tend toward essentialism in their view of risk factors — “lung cancer is a smoker’s disease” — to the neglect of base rates. But the Guardian article frames the lung cancer deaths in non-smokers as a worrying “rise”:

They blame the rise on car fumes, secondhand smoke and indoor air pollution, and have urged people to stop using wood-burning stoves because the soot they generate increases risk… About 6,000 non-smoking Britons a year now die of the disease, more than lose their lives to ovarian or cervical cancer or leukaemia, according to research published on Friday in the Journal of the Royal Society of Medicine.

While the scientific article they are reporting on never explicitly says that lung cancer incidence in non-smokers [LCINS] is increasing, certainly some fault for the confusion may be found there:

the absolute numbers and rates of lung cancers in never-smokers are increasing, and this does not appear to be confounded by passive smoking or misreported smoking status.

This sounds like a serious matter. Except, the source they cite a) doesn’t provide much evidence of this and b) is itself 7 years old, and only refers to evidence that dates back well over a decade. It cites one study that found an increase in LCINS in Swedish males in the 1970s and 1980s, a much larger study that found no change over time in LCINS in the US between 1959 and 2004, and a French study that found rates increasing in women and decreasing in men, concluding finally

An increase in LCINS incidence could be real, or the result of the decrease in the proportion of ever smokers in some strata of the general population, and/or ageing within these categories.

What proportion of lung cancers should we expect to be found in non-smokers? Taking the 11:1 risk ratio, and 15% smoking rate in the UK population, we should actually expect about 85/(15×11)≈52% of lung cancer to occur in non-smokers. Why is it only 1/6, then? The effect of smoking on lu estimated that lung cancer develops after about 30 years of smoking. If we look back at the 35% smoking incidence of the mid 1980s, we would get an estimate of about 65/(35×11)≈17%.

The time lords

The European parliament has voted to stop the practice of switching clocks forward and backward every year, from 2021. I’ve long thought this practice rather odd. Imagine that a government were to pass a law stating that from April 1 every person must wake up one hour earlier than they habitually do, and go to sleep one hour earlier. All shops and businesses are required to open an hour earlier, and to close an hour earlier. The same for schools, universities, and the timing of private lessons and appointments must also be shifted. Obviously ridiculous, even tyrannical. The government has nothing to say about when I go to bed or wake up, when my business is open. But because they enforce it through adjusting the clocks, which seem like an appropriate subject of regulation and standardisation, it is almost universally accepted.

But instead of praising this blow struck for individual freedom and against statist overreach, we have Tories making comments like this:

John Flack, the Conservative MEP for the East of England, said: “We’ve long been aware the EU wants too much control over our lives – now they want to control time itself. You would think they had other things to worry about without wanting to become time lords,” he said, in an apparent reference to the BBC sci-fi drama Doctor Who.

“We agreed when they said the clocks should change across the whole EU on an agreed day. That made sense – but this is a step too far,” Flack added. “I know that farmers in particular, all across the east of England, value the flexibility that the clock changes bring to get the best from available daylight.

So, the small-government Tory thinks it’s a perfectly legitimate exercise of European centralised power to compel shopkeepers in Sicily and schoolchildren in Madrid to adjust their body clocks* in order to spare English farmers the annoyance of having to consciously adjust the clocktime when they get out of bed to tend to their harvest. But to rescind this compulsion, that is insufferably arrogant.

*Nor is this a harmless annoyance. Researchers have found a measurable increase in heart attacks — presumed attributable to reduced sleep — in the days following the spring clock shift. A much smaller decrease may accompany the autumn shift back.

UV radiation and skin cancer — a history

If I had been asked when it first came to be understood that skin cancer is caused by exposure to the sun, I would have said probably the 1970s, maybe 1960s among cognoscenti, before it was well enough established to become part of public health campaigns. But I was just reading this 1953 article by C. O. Nordling on mutations and cancer — proposing, interestingly enough, that cancers are caused by the accumulation of about seven mutations in a cell — which mentions, wholly incidentally, in a discussion of latency periods between the inception of a tumour cell and disease diagnosis

40 years for seaman’s cancer (caused by solar radiation).

So, apparently skin cancer was known to be frequent among sailors, and the link to sun exposure was sufficiently well accepted to be mentioned here parenthetically.

Medical hype and under-hype

New heart treatment is biggest breakthrough since statins, scientists say

I just came across this breathless headline published in the Guardian from last year. On the one hand, this is just one study, the effect was barely statistically significant, and experience suggests a fairly high likelihood that this will ultimately have no effect on general medical practice or on human health and mortality rates. I understand the exigencies of the daily newspaper publishing model, but it’s problematic that the “new research study” has been defined as the event on which to hang a headline. The only people who need that level of up-to-the-minute detail are those professionally involved in winnowing out the new ideas and turning them into clinical practice. We would all be better served if newspapers instead reported on what new treatments have actually had an effect over the last five years. That would be just as novel to the general readership, and far less erratic.

On the other hand, I want to comment on one point of what I see as exaggerated skepticism: The paragraph that summarises the study results says

For patients who received the canakinumab injections the team reported a 15% reduction in the risk of a cardiovascular event, including fatal and non-fatal heart attacks and strokes. Also, the need for expensive interventional procedures, such as bypass surgery and inserting stents, was cut by more than 30%. There was no overall difference in death rates between patients on canakinumab and those given placebo injections, and the drug did not change cholesterol levels.

There is then a quote:

Prof Martin Bennett, a cardiologist from Cambridge who was not involved in the study, said the trial results were an important advance in understanding why heart attacks happen. But, he said, he had concerns about the side effects, the high cost of the drug and the fact that death rates were not better in those given the drug.

In principle, I think this is a good thing. There are far too many studies that show a treatment scraping out a barely significant reduction in mortality due to one cause, which is highlighted, but a countervailing mortality increase due to other causes, netting out to essentially no improvement. Then you have to say, we really should be aiming to reduce mortality, not to reduce a cause of mortality. (I remember many years ago, a few years after the US started raising the age for purchasing alcohol to 21, reading of a study that was heralded as showing the success of this approach, having found that the number of traffic fatalities attributed to alcohol had decreased substantially. Unfortunately, the number of fatalities not attributed to alcohol had increased by a similar amount, suggesting that some amount of recategorisation was going on.) Sometimes researchers will try to distract attention from a null result for mortality by pointing to a secondary endpoint — improved results on a blood test linked to mortality, for instance — which needs to be viewed with some suspicion.

In this case, though, I think the skepticism is unwarranted. There is no doubt that before the study the researchers would have predicted reduction in mortality from cardiovascular causes, no reduction due to any other cause, and likely an increase due to infection. The worry would be that the increase due to infection — or to some unanticipated side effect — would outweigh the benefits.

The results confirmed the best-case predictions. Cardiovascular mortality was reduced — possibly a lot, possibly only slightly. Deaths due to infections increased significantly in percentage terms, but the numbers were small relative to the cardiovascular improvements. The one big surprise was a very substantial reduction in cancer mortality. The researchers are open about not having predicted this, and not having a clear explanation. In such a case, it would be wrong to put much weight on the statistical “significance”, because it is impossible to quantify the class of hypotheses that are implicitly being ignored. The proper thing is to highlight this observation for further research, as they have properly done.

When you deduct these three groups of causes — cardiovascular, infections, cancer — you are left with approximately equal mortality rates in the placebo and treatment groups, as expected. So there is no reason to be “concerned” that overall mortality was not improved in those receiving the drug. First of all, overall mortality was better in the treatment group. It’s just that the improvement in CV mortality — as predicted — while large enough to be clearly not random when compared with the overall number of CV deaths, it was not large compared with the much larger total number of deaths. This is no more “concerning” than it would be, when reviewing a programme for improving airline safety, to discover that it did not appreciably change the total number of transportation-related fatalities.

The world’s easiest job

In six US states — Arizona, Idaho, Arkansas, Georgia, Mississippi, and South Dakota — pharmacists are permitted to refuse to fill prescriptions to which they have moral or religious objections. In Idaho they can still be required to fill the prescription in life-threatening situations if no one else is available, and in Arizona they must at least return the prescription so they can get it filled from another pharmacist. In the other four, apparently they don’t even have to do that much.

So, I’m thinking, there’s hardly an easier job that Christian Scientists, in the last four states particularly, if they’re looking for easy work should apply to pharmacies. No matter what prescription anyone brings to them they can toss it in the bin and go back to playing solitaire, or reading the works of Mary Baker Eddy.

(You may think they’d have difficulties getting hired, and they may indeed have to acquire some formal qualifications. No lunch is completely free, though presumably they can obtain religious exemptions from most of the requirements of their course. But the drug store can’t refuse to hire them on religious grounds.)

Political doping

Who would have imagined that elections could be swayed by political-performance-enhancing drugs?

Trump, in full “unshackled” mode, told a crowd of supporters in Portsmouth, New Hampshire that Clinton, who has won both presidential debates according to most polls, seemed “pumped up” at the beginning of the second debate last Sunday, but that he thought her energy then waned as the debate went on. So, in Donald Trump’s reality, it of course stands to reason that she was thus “pumped up” on some kind of performance-enhancing drugs, and they should both take drug tests before the third debate.

I dispute the claim that this is fully unshackled. If Trump were fully unshackled, he would demand that Clinton be subjected to a medical gender test, like South African runner Caster Semenya. After all, as Trump has so eloquently put it in the past

Frankly, if Hillary Clinton were a man, I don’t think she’d get 5 percent of the vote.

(“Frankly” is great. He’s giving us the straight dope now, as opposed to the politically correct pabulum that he is otherwise forced to espouse.) She should have to prove, then, that she’s not a man. It clearly wouldn’t be fair to allow Hillary Clinton to run for president as a woman, with all the advantages that women are known to enjoy in presidential campaigns, while actually benefitting from a higher testosterone level than her male opponent.

Imagine if it didn’t come out until after the election that Hillary was doping. What would we do then? Would her victory be annulled? Would she be banned from political competition for four years? If her testosterone levels are too high, would she be forced to take suppressing hormones? Would she be required campaign as a man? Perhaps she’d have to sexually assault a campaign worker, to even things out? The mind boggles.

Donald Trump’s prodigious prostate

Let us accept for a moment the claim that Donald Trump’s medical condition is uniformly excellent. You might still expect that random medical test results should be about average for a healthy man. (Not meaning BP or heart rate or god-forbid testosterone, which you would expect to reflect his hyperpowerful masculinity.) I was looking at this report, released a few weeks ago, which included Trump’s test result for PSA (prostate-specific antigen). High levels can be signs of an enlarged prostate, or prostate cancer. But Trump’s doctor reports his level at 0.15. According to this study men over 70 with normal prostate have a median level of 1.9 (it doesn’t seem to depend much on age above 70). If we make the very conservative assumption that the distribution falls off linearly from 1.9 down to 0, we would estimate that less than 1% of men have PSA scores below 0.2.

Maybe Trump has no prostate.

Alternatively, he should really be compared with a younger reference group, because his pact with Mephistopheles and/or regular consumption of the blood of virgins keeps him youthful.

Chinese towels

Another thought about Elizabeth Holmes and Theranos: Her billion-dollar medical-testing company based on secret and unproven technology in her twenties depended largely on a board of well-connected politicians and former politicians, notable for their lack of any relevant scientific expertise. But before she got to that point she needed to turn the heads of some scientists. According to the New Yorker, she caught the attention of dean of engineering Channing Robertson in her freshman year at Stanford:

One day, in her freshman year, Robertson said, she came to his office to ask if she could work in his lab with the Ph.D. students. He hesitated, but she persisted and he gave in. At the end of the spring term, she told him that she planned to spend the summer working at the Genome Institute, in Singapore. He warned her that prospective students had to speak Mandarin.

 “I’m fluent in Mandarin,” she said.

“I’m thinking, What’s next? She’s already coming into the research group meetings at the end of her freshman year with my Ph.D. students. I find myself listening to her more than to them about the next experiments to be done and the progress that’s been made. I realized she’s different.”

Clearly scientific acumen was exceptional. But what is the role of Mandarin? (This is the second story in the article about how she impressed people with her knowledge of the language.) I am reminded of the famous passage in The Hitchhiker’s Guide to the Galaxy:

A towel, it says, is about the most massively useful thing an interstellar hitchhiker can have. Partly it has great practical value… More importantly, a towel has immense psychological value. For some reason, if a strag (strag: non-hitchhiker) discovers that a hitchhiker has his towel with him, he will automatically assume that he is also in possession of a toothbrush, face flannel, soap, tin of biscuits, flask, compass, map, ball of string, gnat spray, wet weather gear, space suit etc., etc. Furthermore, the strag will then happily lend the hitchhiker any of these or a dozen other items that the hitchhiker might accidentally have ”lost”.

Is speaking Mandarin (assuming you’re not yourself Chinese) the intellectual equivalent of having your towel? Is that what he means by “What’s next?” He’s thinking, I’m dean of the engineering school at Stanford, and I don’t speak Mandarin. She’s only 18 and she’s managed to learn to speak fluent Mandarin. She must know all kinds of things that I have no inkling of.

Is that the reason why the chic private schools in the UK all seem to be teaching Mandarin?

How to do it: Medical testing edition

I was commenting just recently on the cult of big ideas, where people whose life experiences have given them hierarchical power are suckers for “ideas” that are mostly blather, lots of words about the irrelevant bits of the problem, distracting attention from the real difficulties. And now Theranos is in the news. I read about this company, started by the obviously charismatic Elizabeth Holmes, in The New Yorker about a year ago. My immediate reaction was, this must be a joke. It was very much in the spirit of Monty Python’s How to do it.

Theranos, a Silicon Valley company[…], is working to upend the lucrative business of blood testing. Blood analysis is integral to medicine. When your physician wants to check some aspect of your health, such as your cholesterol or glucose levels, or look for indications of kidney or liver problems, a blood test is often required. This typically involves a long needle and several blood-filled vials, which are sent to a lab for analysis… [Theranos] has developed blood tests that can help detect dozens of medical conditions, from high cholesterol to cancer, based on a drop or two of blood drawn with a pinprick from your finger. Holmes told the audience that blood testing can be done more quickly, conveniently, and inexpensively, and that lives can be saved as a consequence.

Sounds wonderful. Quick. Convenient. Inexpensive. Saving lives. How is she going to do all that? Well, she wears “a black suit and a black cotton turtleneck, reminiscent of Steve Jobs”. She dropped out of Stanford. She has a board of directors full of highly influential aged former politicians, but no scientists, so far as I can tell. She “is in advanced discussions with the Cleveland Clinic. It has also opened centers in forty-one Walgreens pharmacies, with plans to open thousands more. If you show the pharmacist your I.D., your insurance card, and a doctor’s note, you can have your blood drawn right there…. A typical lab test for cholesterol can cost fifty dollars or more; the Theranos test at Walgreens costs two dollars and ninety-nine cents.” Continue reading “How to do it: Medical testing edition”

The politics of impatience

What does it mean when someone who is himself significantly responsible for solving a problem expresses his “impatience” for a solution? I think of this because today’s Times has on page 2

George Osborne lost patience with the pensions industry yesterday, announcing action against insurers who blocked savers from accessing their cash.

And on page 4 we read of

news of a fresh delay of up to a year in publication of the Iraq inquiry, prompting Mr Cameron to say that he was “fast losing patience”.

Perhaps this outbreak of impatience is somehow related to the front-page story, which says

the very best they can expect is that it will take them time — but time is not on their side.

That one is about the pervasive decline in sperm quality due to plastics in packaging, sunscreens and cosmetics.