Posts in: science

Annus semi-mirabilis

As far as discoveries go, 2023 is shaping up nicely. Yesterday we had electricity from air, today there is some movement on superconductors.

Sure, none of these will be immediately life-changing. But I vaguely remember reading about some new super-slick materials years ago, and today I don’t have to worry about how to get leftover ketchup out from the bottom of the bottle.

Progress!

Air power

From Phys.org:

In this Nature paper, the researchers extracted the enzyme responsible for using atmospheric hydrogen from a bacterium called Mycobacterium smegmatis. They showed that this enzyme, called Huc, turns hydrogen gas into an electrical current. Dr. Grinter notes, “Huc is extraordinarily efficient. Unlike all other known enzymes and chemical catalysts, it even consumes hydrogen below atmospheric levels—as little as 0.00005% of the air we breathe.”

  1. Biotech for the win (?)
  2. Or does this pave the way for a dystopian post-biology future in which insatiable human appetites deplete all hydrogen from the atmosphere?
  3. Mycobacterium smegmatis becoming the savior of humanity and a household name would provide fodder for middle school humor for generations to come.

Yes, there is dire inequality in clinical trial enrollment, but this is the precisely wrong way to address the lack of diversity.

Legislating behavior leads to made-up plans that are at best a waste of an intern’s time and at worst a six-figure donation to “providers” selling their “solutions”. If you will ultimately grade on the outcome — and you should! — well, what do you care how it was achieved, provided that all the other laws and guidances were followed?

Silly, silly games.

Almost 5 years old, but still worth sharing: the first ever video of mating anglerfish.

Most of what we know about deep-sea anglerfish comes from dead animals pulled up in nets. Scientists have identified more than 160 species, but only a handful of videos exist—and this is the first to show a sexually united pair. “So you can see how rare and important this discovery is,” Pietsch says. “It was really a shocker for me.”

Isn’t nature just swell?

March lectures of note

Available to general public!

ChatGPT and Potential Healthcare Implications of Large Language Models

Tests for Early Cancer: Facts vs. Opinions Can We Detect Early Cancer?

It’s a Bacterial World

Bias of the day: immortal time

This is when you do a retrospective study, select cohorts according to exposure, but measure outcomes — usually death, or hospitalization, or something else bad — in a way that guarantees one or more of the cohorts have a period of time when that outcome couldn’t have happened. That’s how you get “immortal”, or “guaranteed” time.

Three classic examples: Courtesy of Bing.

  • A study that evaluated the hypothesis that menopause occurring before age 40 years is associated with the development of cardiovascular disease (CVD). The study counted women who had premature menopause as exposed to CVD risk from their date of birth, ignoring the fact that they could not have developed CVD before menopause.
  • A study that assessed the effect of statins on diabetes progression and insulin use. The study classified patients as statin users based on their first prescription after hospital discharge, but included the time between discharge and prescription as exposed time, even though they were not taking statins during that period.
  • A study that examined the association between beta-blocker use and mortality in patients with heart failure. The study defined beta-blocker exposure based on pharmacy claims after hospitalization, but did not account for the time lag between hospital discharge and drug initiation, which could have biased the results in favor of beta-blockers.

To these three classics we can now add two more, one highly publicized, the other less so, both surprising considering the journals and the supposed peer review they must have gone through:

  • A study that compared hospitalization rates of those who had a positive SARS-CoV-2 test and did not take the Covid-19 drug Paxlovid to those who took Paxlovid regardless of test status. The study counted the day of the positive test as “Day 0” for the untreated cohort; however, for patients who started taking Paxlovid and did not have records of a positive test “Day 0” was one day before treatment start. See this Twitter thread for relevant excerpts and a more detailed explanation. As the study excluded patients who were already hospitalized when they started Paxlovid, but included untreated patients who had a positive test and were hospitalized on the same day, this guaranteed 1 day of “immortal time” for the Paxlovid cohort.
  • A study that used “real world data” to compare standard blood thinners to a procedure called left atrial appendage occlusion (LAAO) for prevention of death and stroke in patients with atrial fibrillation. However, patients who underwent LAAO had to live long enough with atrial fibrillation without getting a stroke to “graduate into” the procedure. Not only is immortal time here so glaring, the study is eerily similar to the original heart transplantation study in which this bias was first identified.

Cardiologist John Mandrola explains in depth why the LAAO paper, and the way it was spun, is particularly egregious.

Note that this is only a problem in retrospective — or, how they now like to be rebranded, “real-world” — studies. As the most recent cases show, these are not only worthless for informing anyone’s real-world decision, but also contribute to the noise, the chaos, and the general fear-uncertainty-doubt of medicine. A voluntary moratorium would not be out of line.

Finished reading: Fundamentals of Clinical Trials by Lawrence M. Friedman 📚

It is assigned reading for a course I’m helping prepare, so I thought I’d better read the book we’ll ask our students to use. Like many textbooks, it suffers from MANE — many authors no editors — and like many academic texts, it can get way too pedantic. Still, it is hard to argue with its overarching themes: that randomized controlled trials are the pinnacle of medical evidence generation, and that much of the trial paperwork done in the name of quality is unnecessary. I have more comments on that last point, but that is for another time.

For Valentine’s Day, The Washington Post decided to write about a promising new male contraceptive drug being studied in mice. That’s fine. What’s unusual, bizarre, and a bit of a troll is hanging a red banner over the front page presenting it as breaking news. Seriously, WaPo?

When Russ Roberts, my favorite interviewer, speaks with Adam Mastroianni, the author of my favorite newsletter, of course I have to share it. No excerpts, just listen to the whole thing, please.

The academic prisoners' dilemma

As of this year, eLife no longer has “accept/reject” decisions after peer review: Which I learned via Andrew Gelman.

All papers that have been peer-reviewed will be published on the eLife website as Reviewed Preprints, accompanied by:

Authors will then receive a paper with a full DOI that can be used on funding applications. They will be able to include a response to the assessment and reviews, and decide what to do next:

  • Revise and resubmit
  • Declare the Reviewed Preprint as the final Version of Record

This is as it should be in the age of unlimited digital space.

The quality of public peer review on eLife seems above average: I have once, as the sole peer review of this paper from a double-digit impact factor journal, Impact factor of eLife, per Wikipedia, is 8.7 received a single sentence which amounted to “sample size too small”, but with more spelling errors and the same lack of punctuation. If your goal when reading a paper is both critical appraisal and learning, you could do worse than reading this exchange.

But! Eleven reviewed preprints total in the last 5 months seems… low? Am I missing other public reviews? I would, for example, very much like to learn what the reviewers said about this.

More generally, I am worried that this will make eLife become the default publication of last resort — trouble for the Infection and Immunity and Leukemia and Lymphomas of the world, but not exactly the killing blow to Science or Nature or most of its million offshoots.

The current, bizarre, inefficient, unsustainable — Byzantine, if you will, thought that is too disrespectful of Byzantium — keeps itself alive through force of reputation. Critical thinking is hard, so unless I am in the opposing team and my goal is to tear down your data I will save many a mental cycle by “trusting the process” and taking the conclusion, abstract, that one piece of information I need to cite in my own work… at face value. And evidence to the contrary be damned, say published in NEJM to a clinician and their ears will perk up.

So we are in a prisoner’s dilemma of sorts. Take a group of one hundred researchers: the average benefit to all of them, and to science in general, would be greater if all published in eLife. But, if 90 of the 100 submit to CNS journals or NEJM first then go down the impact factor list and only 10 shmucks go straight to eLife, there will be only a handful of “winners”, the state of science remains what it is, and everyone ends up wasting so… much… time.

It doesn’t have to be this way – and Covid did expedite some reputational decay – so this is a good a time as any to place a chisel in the crack. What’s needed now is some forceful movement of the hammer and, well, I guess people who publish People who review are equally important, but maybe just maybe we will at one point be able to leave that to an algorithm. It would certainly do a better job than most! are the hammer in this strained analogy.

Should I start with myself? I do have a handful of side projects which are neither industry nor strictly academic — myself having no academic affiliation. Stay tuned.