Wednesday, January 10, 2018

Is evidence-based medicine dead?

kw: book reviews, nonfiction, medicine, medical research, critiques

Research incentives are messed up, big time. So much so that Sturgeon's Law of fiction writing applies, doubled: when someone protested to him about the presentations at a science fiction convention, that 90% of it was crud, he replied, "90% of everything is crud!" When people's careers are on the line, when jobs, promotion, tenure and salary all depend on "Publish or Perish", virtue vanishes. Young, idealistic researchers become jaded, cynical cheaters. One medical author has written that as much as 99% of published medical research is valueless or even damaging. Another wrote,
"One must not underestimate the ingenuity of humans to invent new ways to deceive themselves."
This quote is found on page 192 of Rigor Mortis: How Sloppy Science Creates Worthless Cures, Crushes Hope, and Wastes Billions by Richard Harris. Author Harris admits that his title is a bit tongue-in-cheek, because rigor mortis literally means the stiffness of a corpse, while "rigor" also means strictness in carrying out a procedure. While it might be more accurate to title the book Mortis Rigoris (the death of rigor) or Mortuus est Rigor (rigor has died), it wouldn't resonate with doctors and others of us who know Latin.

More accurately, however, while experimental rigor is neglected more than adhered to, and may be on the ropes, it isn't quite dead yet. The ten chapters in Rigor Mortis illustrate and document every major aspect of medical research, from experimental design (The "gold standard" of the double-blind trial is nearly always compromised to save expenses, and frequently foregone entirely) to animal studies (Suppose you were told that a certain medicine was tested exclusively on women pregnant in their first trimester, of ages between 22 and 25, all from a specific ethnic group in Scandinavia? That's the analogy to a typical mouse study) to statistical analysis (The p-test is dramatically misleading, and we'll get into that one anon).

Have you ever heard of the "desk drawer file"? It is a lot like a Roach Motel; experiments with "negative results" check in, and are never checked out. Some of the few honest researchers left in the field are agitating for a requirement that every study funded with tax dollars be published, no matter what the outcome. The good news: transparency. The bad news: a ten- to 100-fold increase in the number of papers published. There is already an overwhelming deluge of publication! Gack!!

We need look no further than this to validate Sturgeon's Law. Consider the much-overused p-test, or p-value. You take a bunch of numbers, grind the formula (found in every statistical software package out there, including Excel), and out pops a number. Is it smaller than 0.05? Publish! That number gets inverted into "95% statistical probability that the result shown is not due to chance." Hmm. But what is it due to? Sunspots? Batch effects (perform run 1, clean equipment, perform run 2; do they differ because of the cleaning?)? Something you would never think of in your wildest dreams (all too frequently, yes)? But just suppose all those "95% chance it's right, 5% it's wrong" papers actually do have the "correct" cause and effect. How many experiments went to the "desk drawer" since the last time you published? 5, 10, 20, 100? The average is (wait for it) about 20! So, ignoring the desk drawer, five out of 100 publications must be reporting a chance association or correlation. Add the desk drawer factor of 20, and now at least half of them are reporting a correlation due to chance. Just by the way, it is amazing that the vast majority of studies that report a p-value have a number just under 0.05: "Dig around until you get a p-value you like, then stop looking."

Add in other factors, all detailed in Rigor Mortis, and there is little chance that more than a tiny fraction of published research results will stand the test of time. And that is a problem. A little time? That is OK. If a lot of further research and even development and marketing are based on a faulty result, and it takes "medical science" 5, 10, 20 years or more to find and correct the mistake, how many people die or suffer needlessly?

Is there a way out of it? Only partially. Transparency is part of the answer. But bureaucrats are lazy, so even with a law on the books that all studies funded by NIH must publish all results, for example, it is poorly enforced. There are a lot of partial answers out there. Here is my answer: We must live with what we have now, while things are possibly getting better, but today is today. When I must choose a new doctor or specialist, I inspect the waiting room, and later the visitation room. How many drug company trinkets can I find (pens, calendars, note pads, posters, and many more)? The fewer the better. My current doctor's rooms don't have anything with a logo on it. That's a great start; it means the doctor has better-than-usual resistance to high-pressure sales. Such a doctor is more likely to make a decision on medical grounds. Secondly, who do I actually see? Curiously, I prefer to be seen by a PA or NP, rather than a DO or MD. They haven't had all their good sense educated out of them yet. In my experience they are also a lot more willing to answer questions and do so more meaningfully. Also, I do ask a lot of questions, because a brusque doctor is likely to be impatient in the operating room also. In medicine, patience isn't just a virtue, it is a necessity! There is more, but if you aren't doing these things, start there.

What else can you or I do? Educate yourself. Not from medical journals, but from summary materials on things that are known to work. WebMD and Healthline are just the beginning. Don't limit your reading to a single source. When offered a "new" drug, always ask, "Is there an older one that works well enough, perhaps with fewer side effects?" There are always side effects. Some you can live with, some you can't. Do avoid, desperately, a drug that needs another drug to deal with side effects. My wife takes a statin drug for high cholesterol. She was originally prescribed the strongest one, and even taking a tiny dose, had troubling side effects. Her "undrugged" total cholesterol is 240, but that drug is best used for folks in the 400+ range. She demanded a weaker one, and even then, splits the pill in thirds. She has no noticeable side effects, and her "drugged" total cholesterol is about 160. Good enough!

I've learned to tell a doctor, "I am not a patient. I am a customer. You and I will collaborate. I will never cede my right to make decisions, except during anesthesia that we have agreed upon together." Call it an intelligence test. For the doctor. Occasionally a doctor fails it, and then I get another doctor. When needed, I make a doctor aware how skeptical I am of the "evidence" presented in modern journals.

Rigor Mortis is scary. Is it right? Sadly, yes, it is more right than the average published medical study. But don't let that drive you to the amorphous world of "alternative medicine", at least not wholesale. Allopathic medicine has produced amazing health in most Americans and others in the First World. For a generation or so medical research has gone astray. Will it return? Maybe. Until it does, we must be our own best doctors.

Thursday, January 04, 2018

Sleep, beautiful sleep

kw: book reviews, nonfiction, sleep

What a way to start the year! with a book about sleep. Michael McGirr, a former Jesuit priest, and a victim of sleep apnea, writes about sleep and sleeplessness from a few unique perspectives in his book Snooze: The Lost Art of Sleep. I read the book hoping to re-connect with this lost art, but found instead a travelogue, a book of "what" but not "how".

There is no table of contents and I didn't count as I went, but I reckon there are upwards of a dozen chapters. Each is titled by a time and a year (or a few related years), thusly:



in which chapter he writes of his diagnosis of sleep apnea and the invention of the CPAP machine, and about his marriage to Jenny who loved him anyway (this after he left the Jesuit order), or



riffing on Jacob son of Isaac, one of history's celebrated sleepers, he of the dream of angels on a ladder, but one who nonetheless complained to his father-in-law,
… by day the heat consumed me, and the cold by night, and my sleep fled from my eyes.
He writes of Edison, who was too busy inventing to sleep; of Florence Nightingale, who slept little but spent some 3/4 of her life directing matters worldwide from her bed; and of coffee and its use to ward off sleep, so much so that Balzac, who fueled his amazing literary output with sixty cups of coffee daily, died of caffeine poisoning at age 51. Balzac might have lived a lot longer on half the coffee, and while writing less daily, his total production might have been even greater.

I am reminded of Alfréd Rényi, who said, "A mathematician is a machine for turning coffee into theorems," a quote usually attributed to Paul Erdős, and tangentially of Leonardo da Vinci, who is said to have kept to a regimen of three hours and 40 minutes of work followed by a 20-minute nap, day in and day out (that comes to two hours in each 24-hour period). I read about one man who tried working on this schedule and did so for a few years, but then gave it up because he ran out of things to keep him busy. I guess to keep Leonardo's schedule you have to have Leonardo's creativity. I wish McGirr had included these also in his travelogue of sleep and its variations, but he did not.

Regardless, his own studies of sleep, restful or not, led him in many directions, including into those antonyms of caffeine, the various sleep-inducing drugs, from Benadryl® to Ambien® and beyond. During a hospital stay, a nurse gave me two Benadryl®, which worked well. My father used a prescription sleep aid that turned out to be a double dose of diphenhydramine in one pill; the exact equivalent of taking two Benadryl®, but a lot more costly. But the more recent drugs induce sleep by messing with the normal sleep cycle, which can put you into a deep sleep without the total sleep paralysis needed to keep you from acting out your dreams. Lots of sleepwalking (and sleep driving, etc.) incidents are known, some with fatal results.

In the last chapter, he writes that reading in bed can help us drowse, but only if we are reading off of printed paper. The reflected light from a page with dark ink does not inhibit melatonin production. The light from a computer of phone screen has a different quality, and does so interfere.

Overstress is a primary enemy of sleep. We need a certain amount of stress to keep life interesting, but overwhelming, chronic stress just burns us out. Some folks respond with depression and may take to their beds, sleeping much or most of the day. Most of us have trouble getting to sleep, wake too early, and feel tired much of the time. While a few chapters of Snooze address chronic insomnia, a broader affliction is that many of us get some sleep each night, but never seem to get enough. Many, many of us have an experience like mine.

During the last ten or so years of employment at DuPont, I seldom slept more than four hours nightly. For some of that time, I was also on one or another medication to address my bipolarity, but they didn't do much so I learned to cope with it unmedicated. During those medicated periods, I usually napped up to two hours daily, so you could say I had six hours of sleep, but not in one installment. However, without medication with a sleep-promoting side effect, four hours was it. No naps. I had work I enjoyed a lot, a congenial boss (the last 8 of the 10 years), and even told my boss I might work until I was 75. But when the company declared a retirement incentive, I retired at age 66.

After retirement, two important things happened. Within a few weeks, I was sleeping 6-7 hours nightly, and over about half that first year I lost 15 pounds. I remember looking back one day, and saying to myself, "I didn't realize the level of stress I was under!" I had also been using a lot of "cold caffeine" (Pepsi Max), up to a liter daily.

Now that four more years have passed and I am over 70, I get 5-7 hours of sleep, and if I wake early I simply get up, read my Bible a while, have breakfast, then have a morning nap for another hour or two. There aren't a lot of conclusions to draw from that. I am thankful that, though I snore some nights (not all), I don't have apnea; I have part time work that keeps some structure in my life, but is incredibly less stressful than any job I had before; I practically eliminated caffeine, using caffeinated cola only for driving alertness on road trips.

You'll have to look elsewhere for advice and information on how to sleep longer and better. For an enjoyable survey of how humans have been sleeping, or not, Snooze is the book for you.