Category: Methodology

The Curious Still Have a Lot to Learn

(p. 22) Earlier this week, and more than 2,700 feet underwater by the northern Great Barrier Reef, a remotely operated vehicle named SuBastian engaged in a stare-off with a burrito. That’s what the creature looked like from a distance: an untoasted cylinder floating eerily upright in the ocean’s twilight zone, like takeout from Triton.

. . .

When Dr. Vecchione got a good look at the image, he knew exactly what it was: Spirula spirula, or the ram’s horn squid. Spirula is the only living squid to have an internal coiled shell, which it tucks under the fleshy flaps of its rear end, according to Jay C. Hunt, a biologist at East Stroudsburg University. The squid can also emit lime-green light from a large photophore, also located on its behind.

. . .

Although the Spirula sighting may be a scientific first, it did not make a strong initial impression on the researchers onboard. “We’ve seen bobtail squids and dumbo octopuses where we say, ‘Wow, this is the cutest thing,’” Ms. Cornet said. “This one was weird-looking, and looking at us with its weird eye.”

Perhaps even more surprising than the creature’s cameo was its strange positioning. Scientists had always assumed that Spirula swam with its head pointed down and its gas-filled bottom in the air. When Dr. Vecchione caught living Spirulas in trawl nets and plopped them in cold water onboard, the “sort of alive” squids always floated rump-up, he said.

This hypothesis made sense; the squid’s gas-chambered shell buoyed it like a nautilus, after all. But it raised another question. Deeper-living creatures often point their photophores downward, disguising their silhouettes from predators lurking below. Beaming a green light toward the sky, on the other hand, serves no clear purpose. “This is neither common nor does it make sense,” Dr. Vecchione said.

But the Spirula caught on camera was clearly head-up, suggesting that its downward-gazing photophore was most likely used for counterillumination after all. “This makes sense,” Dr. Vecchione said.

Although the photophore mystery may now be solved, a right-side-up Spirula would seem to have a balancing problem, with the squid’s body mass precariously balanced on its buoyant shell. “When you design an R.O.V. you don’t put the heavy stuff on top and the floats on the bottom,” Dr. Lindsay said.

For the full story, see:

Sabrina Imbler. “A Squid Seen in the Wild, Perhaps for the First Time.” The New York Times, First Section (Sunday, November 8, 2020): 22.

(Note: ellipses added.)

(Note: the online version of the story was updated Oct. 31, 2020, and has the title “‘They’re Calling You on the Squid Phone’.” In the last sentence of the first paragraph quoted above, the phrase “like takeout from Triton” appears in the online, but not the print, version.)

“Exhilaration and Loneliness of Pioneering Thought”

(p. A15) In “The Riddle of the Rosetta: How an English Polymath and a French Polyglot Discovered the Meaning of Egyptian Hieroglyphs,” Jed Z. Buchwald and Diane Greco Josefowicz recount Thomas Young’s and Jean-François Champollion’s competing efforts toward decipherment.

. . .

The authors are chiefly concerned with Young’s and Champollion’s approaches to the hieroglyphic riddle. Rarely have I seen the false starts and blind alleys, firm beliefs and 180-degree recalibrations, exhilaration and loneliness of pioneering thought captured so well. On the other hand, not every reader will match Champollion’s stamina or persevere through the book’s densest thickets. Dramatic touches are few. Champollion probably didn’t, as commonly reported, faint at the moment of his triumph. And Young was no swashbuckler. Indiana Jones hates snakes. Young hated idioms.

If “The Riddle of the Rosetta” won’t be coming to screens anytime soon, its achievement is no less admirable. For nearly 500 pages we are invited to inhabit the minds of two of history’s finest linguists.

For the full review, see:

Maxwell Carter. “BOOKSHELF; Found In Translation.” The Wall Street Journal (Friday, September 18, 2020): A15.

(Note: ellipsis added.)

(Note: the online version of the review has the date Sep. 17, 2020, and has the title “BOOKSHELF; ‘The Riddle of the Rosetta’ Review: Found in Translation.”)

The book under review is:

Buchwald, Jed Z., and Diane Greco Josefowicz. The Riddle of the Rosetta: How an English Polymath and a French Polyglot Discovered the Meaning of Egyptian Hieroglyphs. Princeton, NJ: Princeton University Press, 2020.

2016 Law Requires FDA to Move to Mining Real-World Data and Away from Costly and Slow Clinical Trials

(p. A1) Drugmakers are trying to win drug approvals by parsing vast data sets of electronic medical records, shifting away from lengthy, and costly, clinical trials in patients.

. . .

For the companies, the use of real-world data can cut costs and shorten drug-development times. Instead of finding trial subjects, companies simply mine hospital and doctor files for cases where patients already took a drug in routine medical care, looking for changes in blood pressure, tumor size and other readings to see if the medicine is helping or causing a side effect.

. . .

(p. A2) . . . for rare diseases especially, it can take a while to even enroll enough patients in studies. And their cost can limit the number of trials that companies can fund, drugmakers say.

A 2016 law required the FDA to explore greater use of real-world data, and the agency is developing standards to assess the reliability of different data sources and which kinds of decisions the data support.

“Real-world evidence should not be a means toward dropping standards, but rather a mechanism to have more efficiency in evidence generation while maintaining standards,” said FDA Principal Deputy Commissioner Amy Abernethy, a former executive at health-data firm Flatiron Health.

A market has emerged in recent years for digital drug-use information. Iqvia Inc., which tracks prescription and health data, has about a dozen projects under way, said Nancy Dreyer, the company’s chief scientific officer of real-world evidence.

For the full story, see:

Peter Loftus. “Drugmakers Mine Data to Avoid Clinical Trials.” The Wall Street Journal (Tuesday, Dec. 24, 2019): A1-A2.

(Note: ellipses added.)

(Note: the online version of the story was updated Dec. 23, 2019, and has the title “Drugmakers Turn to Data Mining to Avoid Expensive, Lengthy Drug Trials.”)

Mathematical Disciplines Need the “Re-injection” of “Empirical Ideas”

(p. C4) Mathematicians have faced a similar choice between pure and applied work for millennia. In his 1940 book “A Mathematician’s Apology,” G.H. Hardy made a hard-core case for purity: “But is not the position of an ordinary applied mathematician in some ways a little pathetic?…‘Imaginary’ universes are so much more beautiful than this stupidly constructed ‘real’ one.”

On the other hand, John von Neumann rebuked purity in his 1947 essay “The Mathematician”: “As a mathematical discipline travels far from its empirical source…it is beset with very grave dangers. It becomes more and more purely aestheticizing,…whenever this stage is reached, the only remedy seems to me to be the rejuvenating return to the source: the re-injection of more or less directly empirical ideas.”

I think von Neumann has the better of this argument. In his own career, he used his mathematical talents to pioneer fields like game theory and computer science, leaving a titanic legacy, practical as well as intellectual.

For the full commentary, see:

Frank Wilczek. “WILCZEK’S UNIVERSE; Beautiful, Impractical Physics.” The Wall Street Journal (Saturday, Oct. 31, 2020): C4.

(Note: ellipses in original.)

(Note: the online version of the commentary has the date October 29, 2020, and has the same title as the online version.)

The John von Neumann essay mentioned above is:

Neumann, John von. “The Mathematician.” In Works of the Mind, edited by Robert B. Heywood. Chicago: University of Chicago Press, 1947, pp. 180-96.

Costs and Difficulties of Clinical Trials Delay “Most Promising Experimental Drugs”

(p. A6) As the coronavirus pandemic continues to wreak havoc in the United States and treatments are needed more than ever, clinical trials for some of the most promising experimental drugs are taking longer than expected.

Researchers at a dozen clinical trial sites said that testing delays, staffing shortages, space constraints and reluctant patients were complicating their efforts to test monoclonal antibodies, man-made drugs that mimic the molecular soldiers made by the human immune system.

As a result, once-ambitious deadlines are slipping. The drug maker Regeneron, which previously said it could have emergency doses of its antibody cocktail ready by the end of summer, has shifted to talking about how “initial data” could be available by the end of September [2020].

And Eli Lilly’s chief scientific officer said in June that its antibody treatment might be ready in September, but in an interview this week, he said he now hopes for something before the end of the year.

“Of course, I wish we could go faster — there’s no question about that,” said the Eli Lilly executive, Dr. Daniel Skovronsky. “I guess in my hopes and dreams, we enroll the patients in a week or two, but it’s taking longer than that.”

For the full story, see:

Katie Thomas. “Clinical Trials of Drugs For Virus Are Delayed By a Swamped System.” The New York Times (Saturday, August 15, 2020): A6.

(Note: bracketed year added.)

(Note: the online version of the story has the date Aug. 14, 2020, and has the title “Clinical Trials of Coronavirus Drugs Are Taking Longer Than Expected.”)

Bayesian Updating, Not Clinical Trials, Is Key to Advancing Medical Knowledge

(p. D8) In the early pandemic era, for instance, airborne transmission of Covid-19 was not considered likely, but in early July the World Health Organization, with mounting scientific evidence, conceded that it is a factor, especially indoors. The W.H.O. updated its priors, and changed its advice.

This is the heart of Bayesian analysis, named after Thomas Bayes, an 18th-century Presbyterian minister who did math on the side. It captures uncertainty in terms of probability: Bayes’s theorem, or rule, is a device for rationally updating your prior beliefs and uncertainties based on observed evidence.

. . .

As Marc Lipsitch, an infectious disease epidemiologist at Harvard, noted on Twitter, Bayesian reasoning comes awfully close to his working definition of rationality. “As we learn more, our beliefs should change,” Dr. Lipsitch said in an interview.

. . .

But there is little point in trying to establish fixed numbers, said Natalie Dean, an assistant professor of biostatistics at the University of Florida.

“We should be less focused on finding the single ‘truth’ and more focused on establishing a reasonable range, recognizing that the true value may vary across populations,” Dr. Dean said. “Bayesian analyses allow us to include this variability in a clear way, and then propagate this uncertainty through the model.”

. . .

Joseph Blitzstein, a statistician at Harvard, delves into the utility of Bayesian analysis in his popular course “Statistics 110: Probability.” For a primer, in lecture one, he says: “Math is the logic of certainty, and statistics is the logic of uncertainty. Everyone has uncertainty. If you have 100 percent certainty about everything, there is something wrong with you.”

By the end of lecture four, he arrives at Bayes’s theorem — his favorite theorem because it is mathematically simple yet conceptually powerful.

“Literally, the proof is just one line of algebra,” Dr. Blitzstein said. The theorem essentially reduces to a fraction; it expresses the probability P of some event A happening given the occurrence of another event B.

“Naïvely, you would think, How much could you get from that?” Dr. Blitzstein said. “It turns out to have incredibly deep consequences and to be applicable to just about every field of inquiry” — from finance and genetics to political science and historical studies. The Bayesian approach is applied in analyzing racial disparities in policing (in the assessment of officer decisions to search drivers during a traffic stop) and search-and-rescue operations (the search area narrows as new data is added). Cognitive scientists ask, ‘Is the brain Bayesian?’ Philosophers of science posit that science as a whole is a Bayesian process — as is common sense.

. . .

Even with evidence, revising beliefs isn’t easy. The scientific community struggled to update its priors about the asymptomatic transmission of Covid-19, even when evidence emerged that it is a factor and that masks are a helpful preventive measure. This arguably contributed to the world’s sluggish response to the virus.

. . .

In 1650, Oliver Cromwell, Lord Protector of the Commonwealth of England, wrote in a letter to the Church of Scotland: “I beseech you, in the bowels of Christ, think it possible you may be mistaken.”

In the Bayesian world, Cromwell’s law means you should always “keep a bit back — with a little bit of probability, a little tiny bit — for the fact that you may be wrong,” Dr. Spiegelhalter said. “Then if new evidence comes along that totally contradicts your main prior belief, you can quickly ditch what you thought before and lurch over to that new way of thinking.”

“In other words, keep an open mind,” said Dr. Spiegelhalter. “That’s a very powerful idea. And it doesn’t necessarily have to be done technically or formally; it can just be in the back of your mind as an idea. Call it ‘modeling humility.’ You may be wrong.”

For the full story, see:

Siobhan Roberts. “Thinking Like an Epidemiologist.” The New York Times (Tuesday, August 4, 2020): D8.

(Note: ellipses added.)

(Note: the online version of the story has the same date as the print version, and has the title “How to Think Like an Epidemiologist.”)

“The Concept of Microaggressions” Is “Subjective by Nature”

(p. 25) Scott Lilienfeld, an expert in personality disorders who repeatedly disturbed the order in his own field, questioning the science behind many of psychology’s conceits, popular therapies and prized tools, died on Sept. 30 [2020] at his home in Atlanta.

. . .

He . . . received blowback when he touched a nerve. In 2017, he published a critique of the scientific basis for microaggressions, described as subtle and often unwitting snubs of marginalized groups. (For instance, a white teacher might say to a student of color, “My, this essay is so articulate!”) Dr. Lilienfeld argued that the concept of microaggressions was subjective by nature, difficult to define precisely, and did not take into account the motives of the presumed offender, or the perceptions of the purported victim. What one recipient of the feedback might consider injustice, another might regard as a compliment.

The nasty mail rolled in, from many corners of academia, Dr. Lilienfeld told colleagues.

“There was no one like him in this field,” said Steven Jay Lynn, a psychology professor at Binghamton and a longtime collaborator. “He just had this abiding faith that science could better us, better humankind; he saw his championing as an opportunity to make a difference in the world. He enjoyed stepping into controversial areas, it’s true, but the motives were positive.”

For the full obituary, see:

Benedict Carey. “Scott Lilienfeld, 59, Psychologist Who Questioned Science of Psychology, Dies.” The New York Times, First Section (Sunday, October 18, 2020): 25.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the obituary has the date Oct. 16, 2018, and has the title “Scott Lilienfeld, Psychologist Who Questioned Psychology, Dies at 59.”)

Expense of Clinical Trials Reduce the Incentive to Re-Purpose Old, Cheap, Off-Patent Vaccines

(p. A5) “Retrospective studies are great and they provide some hints, but there are caveats,” said Dr. Shyam Kottilil, a professor of medicine with the Institute of Human Virology at the University of Maryland School of Medicine. “It’s very difficult to establish causality.”

Interest in the cross-protective effects of vaccines has led to efforts to repurpose old vaccines that may have potential to provide at least transient protection against the coronavirus until a specific vaccine against SARS-CoV-2 is developed and proven safe and effective, he said.

“But nobody knows whether this approach will work unless we test them,” Dr. Kottilil said. “To endorse this, you need to do really good randomized clinical trials.” There is little incentive for private companies to invest in expensive trials because the old vaccines are cheap and off-patent, he added.

For the full story, see:

Roni Caryn Rabin. “Are Past Vaccinations a Shield? It’s Doubtful.” The New York Times (Thursday, July 30, 2020): A5.

(Note: the online version of the story has the date July 29, 2020, and has the title “Old Vaccines May Stop the Coronavirus, Study Hints. Scientists Are Skeptical.”)

Arthur Ashton’s Serendipitous Invention of Optical Tweezers

(p. B11) Arthur Ashkin, a physicist who was awarded a 2018 Nobel Prize for figuring out how to harness the power of light to trap microscopic objects for closer study, calling his invention optical tweezers, died on Sept. 21 [2020] at his home in Rumson, N.J.

. . .

Dr. Ashkin’s discovery was serendipitous.

In 1966, he was head of the laser research department at Bell Labs, the storied New Jersey laboratory founded by the Bell Telephone Company in 1925, when he went to a scientific conference in Phoenix. There, in a lecture, he heard two researchers discuss something odd that they had found while studying lasers, which had been invented six years earlier: They had noticed that dust particles within the laser beams careened back and forth. They theorized that light pressure might be the cause.

Dr. Ashkin did some calculations and concluded that this was not the cause — it was most likely thermal radiation. But his work reignited a childhood interest in the subject of light pressure.

Light pushes against everything, including people, because it comprises tiny particles called photons. Most of the time the pressure is utterly insignificant; people, for one, feel nothing. But Dr. Ashkin thought that if objects were small enough, a laser might be used to push them around.

. . .

Then, in 1986, he and several colleagues, notably Steven Chu, achieved the first practical application of optical tweezers when they sent a laser through a lens to manipulate microscopic objects. Their results were published in another paper in Physical Review Letters. Dr. Chu began using the tweezers to cool and trap atoms, a breakthrough for which he was awarded a one-third share of the Nobel Prize in Physics in 1997.

Dr. Ashkin, it was clear, was irked that the Nobel committee had not recognized his foundational work in awarding the prize. But he had already begun to use the tweezers for a different purpose: trapping live organisms and biological material.

Other scientists thought this application would not work, as he explained in an interview with the Nobel Institute after he was awarded the prize in 2018.

“They used light to heal wounds, and it was considered to be deadly,” he said. “When I described catching living things with light, people said, ‘Don’t exaggerate, Ashkin.’”

. . .

Dr. Ashkin was awarded one-half the 2018 physics prize, . . . . In so doing he became, at 96, the oldest recipient of a Nobel Prize at the time.

. . .

Dr. Ashkin’s retirement from Bell Labs did not stop him from continuing his research. When he received word of his Nobel Prize, he was working on a project in his basement to improve solar energy collection. Asked if he was going to celebrate, he said: “I am writing a paper right now. I am not about celebrating old stuff.”

For the full obituary, see:

Dylan Loeb McClain. “Arthur Ashkin, 98, Dies; Nobel-Winning Physicist.” The New York Times (Tuesday, September 29, 2020): B11.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the obituary was updated Oct. 5, 2020, and has the title “Arthur Ashkin, 98, Dies; Nobel Laureate Invented a ‘Tractor Beam’.”)

The essay about Aoyagi mentioned above is:

Severinghaus, John W. “Takuo Aoyagi: Discovery of Pulse Oximetry.” Anesthesia & Analgesia 105, no. 6 (Dec. 2007): S1-S6.

“Greatness in Science Often Comes From the Well-Prepared Mind Turning a Chance Observation Into a Major Discovery”

(p. 27) Takuo Aoyagi, a Japanese engineer whose pioneering work in the 1970s led to the modern pulse oximeter, a lifesaving device that clips on a finger and shows the level of oxygen in the blood and that has become a critical tool in the fight against the novel coronavirus, died on April 18 [2020] in Tokyo.

. . .

Mr. Aoyagi’s contribution to medical science was built on decades of innovation and invention. In an essay about Mr. Aoyagi, John W. Severinghaus, a professor emeritus of anesthesia at the University of California, San Francisco, wrote in 2007 that Mr. Aoyagi’s “dream” had been to detect oxygen saturation levels without having to draw blood.

. . .

But he soon ran into a problem. Blood does not flow smoothly like an open tap, but pulses through the body irregularly, thus preventing an accurate recording of dye levels. The problem, however, turned out to be an opportunity. By devising a mathematical formula to correct for this “pulsatile noise,” he created a device that measured oxygen levels with greater accuracy than before.

“Greatness in science, often, as here, comes from the well-prepared mind turning a chance observation into a major discovery,” Dr. Severinghaus wrote.

For the full obituary, see:

John Schwartz and Hikari Hida. “Takuo Aoyagi, 84; Invented Medical Device.” The New York Times, First Section (Sunday, May 3, 2020): 27.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the obituary was updated June 20, 2020, and has the title “Takuo Aoyagi, an Inventor of the Pulse Oximeter, Dies at 84.”)

The essay about Aoyagi mentioned above is:

Severinghaus, John W. “Takuo Aoyagi: Discovery of Pulse Oximetry.” Anesthesia & Analgesia 105, no. 6 (Dec. 2007): S1-S6.

“You Can’t Wait for Somebody to Make a Giant Study”

(p. A6) In April [2020], researchers published an article in the Journal of the American Medical Association suggesting many Covid-19 patients with respiratory distress might require a different treatment approach than typically used for ARDS.

. . .

Maurizio Cereda, an anesthesiologist and head of the surgical ICU at the Hospital of the University of Pennsylvania, said doctors normally use standardized tables to match the level of oxygen in the blood with the amount of PEEP needed. Penn tends to use a table with lower PEEP values, he said, but even those lower levels seem to damage the lungs of some of his Covid-19 patients. As a result, he disregards the table entirely at times, he said, even though some in his institution disagree with his approach.

“You can’t wait for somebody to make a giant study,” Dr. Cereda said. “You are alone with your clinical observation. A lot of people don’t feel comfortable with that because they want to have big guidelines. People seem to be afraid they’re going to do something wrong.”

. . .

At Maimonides Medical Center in Brooklyn, critical-care and emergency-medicine doctor Cameron Kyle-Sidell said he was initially seeing much higher mortality rates from Covid19 patients on ventilators than he would have expected from classic ARDS, possibly because physicians were sticking to PEEP levels used to treat traditional ARDS.

“There are people who are treating this the way they would have treated any other ARDS,” he said. “Then there’re people on the flip side—and I am on that flip side—that think you should treat it as a different disease than we treated in the past.”

For the full story, see:

Sarah Toy and Mark Maremont. “Doctors Split on Best Way To Treat Coronavirus Cases.” The Wall Street Journal (Thursday, July 2, 2020): A6.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the story has the date July 1, 2020, and has the title “Months Into Coronavirus Pandemic, ICU Doctors Are Split on Best Treatment.” The online version quoted above includes a couple of added sentences quoting Dr. Cereda, beyond the single sentence quoted in the print version.)