Category: Methodology

A Map as Large as the Territory It Represents

(p. A4) As more reliable data comes in, said Dr. Spiegelhalter, “the Covid-19 pandemic is rapidly becoming a constrained problem.”

. . .

Statistical science, he said, “is a machine, in a sense, to turn the variability that we see in the world — the unpredictability, the enormous amount of scatter and randomness that we see around us — into a tool that can quantify our uncertainty about facts and numbers and science.”

But as he acknowledged in his book, “The Art of Statistics,” models “are simplifications of the real world — they are the maps not the territory.” (This is reminiscent of Jorge Luis Borges’s story, “On Exactitude in Science,” about a map growing as large as the territory it was meant to represent.)

For the full review, see:

Siobhan Roberts. “Embracing the Uncertainties of the Pandemic.” The New York Times (Wednesday, April 8, 2020): A4.

(Note: ellipsis added.)

(Note: the online version of the review has the date April 7, and has the title “Embracing the Uncertainties.”)

The Spiegelhalter book mentioned above, is:

Spiegelhalter, David. The Art of Statistics: How to Learn from Data. New York: Basic Books, 2019.

“A Clinical Hunch by a Lot of Really Smart People”

(p. A1) Thomas Oxley wasn’t even on call the day he received the page to come to Mount Sinai Beth Israel Hospital in Manhattan. There weren’t enough doctors to treat all the emergency stroke patients, and he was needed in the operating room.

The patient’s chart appeared unremarkable at first glance. He took no medications and had no history of chronic conditions. He had been feeling fine, hanging out at home during the lockdown like the rest of the country, when suddenly, he had trouble talking and moving the right side of his body. Imaging showed a large blockage on the left side of his head.

Oxley gasped when he got to the patient’s age and covid-19 status: 44, positive.

The man was among several recent stroke patients in their 30s to 40s who were all infected with the novel coronavirus. The median age for that type of severe stroke is 74.

As Oxley, an interventional neurologist, began the procedure to remove the clot, he observed something he had never seen before. On the monitors, the brain typically shows up as a tangle of black squiggles – “like a can of spaghetti,” he said – that provide a map of blood vessels. A clot shows up as a blank spot. As he used a needlelike device to pull out the clot, he saw new clots forming in real-time around it.

“This is crazy,” he remembers telling his boss.

A SURGE

Reports of strokes in the young and middle-aged – not just at Mount Sinai but in many other hospitals in communities hit hard by the coronavirus – are the latest twist in our evolving understanding of its connected disease, covid-19. Even as the virus has infected nearly 2.8 million people worldwide and killed 195,000 as of Friday, its biological mechanisms continue to elude top scientific minds. Once thought to be a pathogen that primarily attacks the lungs, it has turned out to be a much more formidable foe – impacting nearly every major organ system in the body.

Until recently, there was little hard data on strokes and covid-19.

There was one report out of Wuhan, China, that showed that some hospitalized patients had experienced strokes but many of those were seriously ill and elderly. But the linkage was considered more of “a clinical hunch by a lot of really smart people,” said Sherry H-Y Chou, a University of Pittsburgh Medical Center neurologist and critical care doctor.

Now for the first time, three large U.S. medical centers are preparing to publish data on the stroke phenomenon. The numbers are small, only a few dozen per location, but they provide new insights into what the virus does to our bodies.

For the full story, see:

Ariana Eunjung Cha. “Strokes Are Striking Younger, Symptomless COVID-19 Victims.” The Washington Post (Saturday, April 25, 2020): A1.

(Note: bold in original.)

(Note: some of the above quote may have been continued onto a later page than A1.)

Seeing Patterns Is Important Knowledge

Collecting, categorizing, and taxonomizing, are early steps toward scientific knowledge, as the example below illustrates. But these activities are often dismissed or ridiculed by members of the scientific establishment.

(p. A23) In the 1970s, Dr. Melzack turned to another problem he had been thinking about for years: pain measurement. At the time, doctors had only very crude instruments, like simply asking people to rate their pain level on a scale from 1 to 10 (a method that is still in use). As a young researcher, Dr. Melzack had worked in a chronic pain clinic and befriended a 70-year-old woman with diabetes.

“She was a highly intelligent person with a good vocabulary, and I began to collect her descriptive words about pain, like ‘burning,’ ‘shooting,’ ‘horrible’ and ‘excruciating,’” he told McGill Reporter in a 2008 interview.

He continued to build his adjective collection by listening to many patients’ descriptions and, working with a statistician, divided them into 20 categories, each describing a particular kind of pain: “tugging,” “pulling” and “wrenching” in one category, for instance, and “pinching,” “pressing” and “gnawing” in another.

This descriptive catalog, published in the journal Pain in 1975, became the McGill Pain Questionnaire. It soon became a standard measure worldwide, deeply enriching the conversations doctors have with their patients, and in many cases helping with diagnosis.

For the full obituary, see:

Benedict Carey. “Ronald Melzack, Cartographer of Pain, Is Dead at 90.” The New York Times (Monday, January 13, 2020): A23.

(Note: the online version of the obituary has the date Jan. 12, 2020, and has the same title as the print version.)

Those in Their 80s, Ceteris Paribus, Less Likely to Be Offered Bypass Surgery

(p. B6) A U.S. study out Wednesday finds that heart attack patients who turned 80 within the previous two weeks were less likely to get bypass surgery than those who were two weeks shy of that birthday, even though the age difference is less than a month.

Guidelines do not limit the operation after a certain age, but doctors may be mentally classifying people as being “in their 80s” and suddenly much riskier than those “in their 70s,” said the study leader, Dr. Anupam Jena of Harvard Medical School.

. . .

Death rates during the first two months after the heart attack were higher among those over 80, suggesting they might have been harmed by not being offered surgery, Jena said.

For the full story, see:

Marilynn Marchione / The Associated Press. “80 Is Not the New 70: Study Finds That Your Age May Bias Heart Care.” The Omaha World-Herald (Wednesday, February 20, 2020): 3A.

(Note: ellipsis added.)

(Note: the online version of the story has the same date as the print version, and has the title “80 Is Not the New 70: Age May Bias Heart Care, Study Finds.” Where there are slight differences in the wording of the online and print versions, the passages quoted above follow the online version.)

Study Claims 77% of Economic Growth is Due to Incremental Innovation

I am surprised by, and dubious of, the claim that 77% of economic growth comes from incremental innovation. That implies that leapfrog innovation, or creative destruction, is not very important. I will need to read and ponder the study that claimed that result.

(p. A15) The comparison of two potential options—known as A/B testing—is now routinely baked into the development of customer-facing software, Mr. Thomke reports. Microsoft, Amazon, Facebook and Google “each conduct more than ten thousand online experiments annually,” he writes, adding that even companies without tech roots (Nike, State Farm) run trials like this regularly. The tests might evaluate, say, the components of a website—style of font, color of background, shape of buttons, choice of words—and continuously adjust them based on user response.  . . .

As much as Mr. Thomke, a Harvard Business School professor, believes that “all businesses should be experimenters,” he wisely observes that “not all innovation decisions can be tested.” A/B testing may not be the best way to evaluate a completely new product or a radically different business model, he concedes, but the approach is the ideal driver of small changes. Though we celebrate disruption, Mr. Thomke urges companies to “tap into the power of high-velocity incrementalism,” explaining that “most progress is achieved by implementing hundreds or thousands of minor improvements.” He points to a study that attributes 77% of economic growth to improvements in existing products and notes that the structured system of incremental improvements that Lego implemented following its near-bankruptcy in 2004 drove 95% of annual sales and helped restore the company to profitability.

For the full review, see:

David A. Shaywitz. “Test, Test And Test Again.” The Wall Street Journal (Monday, March 16, 2020): A15.

(Note: ellipsis added.)

(Note: the online version of the review has the date March 15, 2020, and has the title “BOOKSHELF; ‘Experimentation Works’ and ‘The Power of Experiments’ Review: Test, Test and Test Again.”)

The book discussed in the passages quoted above, is:

Thomke, Stefan H. Experimentation Works: The Surprising Power of Business Experiments. Boston, MA: Harvard Business Press, 2020.

The “study” mentioned above that attributes 77% of economic growth to incremental innovation, is:

Garcia-Macia, Daniel, Chang-Tai Hsieh, and Peter J. Klenow. “How Destructive Is Innovation?” Econometrica 87, no. 5 (Sept. 2019): 1507-41.

Muyembe Had Knowledge of an Ebola Cure Before Clinical Trial

(p. A1) In a medical breakthrough that compares to the use of penicillin for war wounds, two new drugs are saving lives from the virus and helping uncover tools against other deadly infectious diseases. They were proven effective in a gold-standard clinical trial conducted by an international coalition of doctors and researchers in the middle of armed violence.

. . .

(p. A10) Dr. Muyembe set out on his path to an Ebola treatment during the 1995 outbreak. He transferred blood from five survivors to eight patients, hoping that the antibodies that kept some people alive would keep others from dying. Seven of the patients who received the blood transfusion recovered.

He published the results in a scientific journal in 1999. Other researchers said the study was small and had failed to include a control group, a comparison set of patients who weren’t given the treatment, to fully test its efficacy.

For the full story, see:

Betsy McKay. “From a War Zone Came an Unexpected Cure for Ebola.” The Wall Street Journal (Thursday, October 31, 2019): A1 & A10.

(Note: ellipsis added.)

(Note: the online version of the story has the date Oct. 30, 2019, and has the title “‘Ebola Is Now a Disease We Can Treat.’ How a Cure Emerged From a War Zone.”)

“Our Creative Yield Increases with Age”

(p. C1) . . . precocious achievement is the exception, not the norm. The fact is, we mature and develop at different rates. All of us will have multiple cognitive peaks throughout our lives, and the talents and passions that we have to offer can emerge across a range of personal circumstances, not just in formal educational settings focused on a few narrow criteria of achievement. Late bloomers are everywhere once you know to look for them.

. . .

What about creativity and innovation? That realm must belong to the young, with their exuberance and fresh ideas, right? Not necessarily. For instance, the average age of scientists when they are doing work that eventually leads to a Nobel Prize is 39, according to a 2008 Northwestern University study. The average age of U.S. patent applicants is 47.

Our creative yield increases with age, says Elkhonon Goldberg, a clinical professor of neurology at New York University. Dr. Goldberg thinks that the brain’s right and left hemispheres are connected by a “salience network” that helps us to evaluate novel perceptions from the right side by comparing them to the stored images and patterns on our left side. Thus a child will have greater novel perceptions than a middle-aged adult but will lack the context to turn them into creative insights.

Take Ken Fisher, who today runs Fisher Investments, a stock fund with $100 billion under management and 50,000 customers. After graduating from high school, he flunked out of a junior college. “I had no particular direction,” he said. He went back to school to study forestry, hoping for a career outdoors, but switched to economics and got his degree in 1972. In his early 20s, he hung out his shingle as a financial adviser, following his father’s career. To bring in extra money, he took construction jobs, and he played slide guitar in a bar. But he also read and read: “Books about management and business—and maybe thirty trade magazines a month for years,” he says. By the time he reached his 30s, an idea had gelled that would make him his fortune. As he puts it, during that period of reflection, “I developed a theory about valuing companies that was a bit unconventional.”

For the full commentary, see:

Rich Karlgaard. “It’s Never Too Late to Start a Brilliant Career; Our obsession with early achievement shortchanges people of all ages. Research shows that our brains keep developing deep into adulthood and so do our capabilities.” The Wall Street Journal (Saturday, May 4, 2019): C1-C2.

(Note: ellipses added.)

(Note: the online version of the commentary has the date May 3, 2019, and has the same title as the print version.)

The the passages quoted above, are from a commentary that is adapted from:

Karlgaard, Rich. Late Bloomers: The Power of Patience in a World Obsessed with Early Achievement. New York: Currency, 2019.

The research by Elkhonon Goldberg, mentioned above, is described in:

Goldberg, Elkhonon. Creativity: The Human Brain in the Age of Innovation. New York: Oxford University Press, 2018.

Genetic Diversity Limits Number of Patients for Large Randomized Trials

(p. A9) . . . in the era of personalized medicine, where care can be tailored to a person’s genetic make-up and doctors analyze a patient’s DNA to figure out treatments, big trials are falling out of favor.

. . .

To Ursula Matulonis, who treats ovarian cancer and other women’s cancers at Dana-Farber Cancer Institute in Boston, the debate over trial size has a special urgency: Many of her patients are desperately sick.

“You can’t wait years to get these medications approved. What we are dealing with are women with cancers and their lifespans are limited. They need medications and they need them now, and they are not looking to wait for five years,” says Dr. Matulonis, chief of gynecologic oncology.

That is why flexibility in a trial’s size is crucial, she contends. “As we become more genetically astute, and understand a type of cancer better, I think those large randomized trials will be hard to do. There won’t be that many patients,” that fit into one big group, she added.

One of her patients, Janet Sheehan, is grateful for the small clinical trial she has taken part in for the past five years. Ms. Sheehan, a 63-year-old nurse near Boston, was diagnosed with advanced ovarian cancer a dozen years ago. It has come back three times, and at one point she learned that she had a mutation in the BRCA1 gene which indicates a strong predisposition to breast and ovarian cancer. Dana-Farber suggested in 2013 that she go on a randomized 90-person trial for a drug named Olaparib that showed promise among women with a BRCA1 gene mutation.

She has been taking capsules twice a day and going for check-ups every 28 days since then. Despite side-effects, she has been able to work and carry on. “I have seen my children [grow] and I have seen grandchildren I didn’t have then,” she says. Ms. Sheehan was on a randomized trial where both groups of patients received treatment with Olaparib. One group got the drug only, the other received Olaparib in combination with another drug, her doctor said, adding, “there was no placebo.”

In remission, Ms. Sheehan has become a fan of small trials that offer women such as herself options. She also is a realist. If Olaparib fails, she hopes other trials now going on may yield treatments for her.

For the full commentary, see:

Lucette Lagnado. “Is the Big Clinical Trial Obsolete? The New York Times (Wednesday, May 30, 2018): A9-A10.

(Note: ellipses added; bracketed word in original.)

(Note: the online version of the commentary has the date May 29, 2018, and has the title “Are Big Clinical Trials Relevant? Researchers Disagree.” The sentence that starts with “In remission,” was in the online version, but not the print version. )

Mandated Long Clinical Trials Favor Trivial Incremental Drugs and Impede Magic Bullet Cures

(p. B1) AstraZeneca PLC’s new cancer research chief, José Baselga, wants the company to prioritize early-stage cancers over advanced disease when developing new cancer drugs. If successful, his unorthodox strategy could reap rewards for both patients—the potential to cure cancer is much greater when it is treated early—and company coffers.

The approach turns the tried-and-tested model of cancer drug development on its head. Typically, drug companies aim their new cancer drugs at patients with advanced forms of the disease who have exhausted other treatment options. Of the more than 30 new drugs for solid tumors approved for sale in the U.S. since the start of 2014, just two targeted early cancer.

That is largely because there is a clear-cut case for testing new drugs on patients with advanced cancer, as they don’t have other options. What’s more, measuring a new medicine’s effect in advanced cancer is straightforward: a meaningful extension in survival can usually be measured in months. Such patients are also often more willing to try experimental drugs, and regulators have smoothed the path for treatments that show they can prolong lives by delaying tumor growth in advanced cancer.

. . .

(p. B5) “One thing with early stage disease, you have to be able to cure patients,” said Daniel Chen, who spent more than a decade running cancer drug development projects at Roche Holding AG. “The majority of cancer drugs delay cancer growth, they don’t cure patients.” Dr. Chen is now chief medical officer at biotech startup IGM Biosciences Inc.

Running clinical trials could also be difficult, as it would involve persuading patients to try experimental drugs when they might already be cured.

Another challenge is measuring the drug’s effectiveness. In patients whose cancer is diagnosed and treated early, it would take years to determine whether a new drug meaningfully extended survival, making for very long clinical trials.

For the full story, see:

Denise Roland. “Drug Giant Tests Bold Tactic to Battle Cancer.” The Wall Street Journal (Tuesday, May 28, 2019): B1 & B5.

(Note: ellipsis added.)

(Note: the online version of the story has the date May 27, 2019, and has the title “Drug Giant Tries New Tactic to Fight Cancer.”)

Sulston Earned Nobel, Not by “Bold Theories,” But by “Gathering Data for the Sake of Seeing the Whole Picture”

(p. A9) The nematode worm known as C. elegans is only a millimeter long and leads what appears to be a fairly dull existence. It eats bacteria, wriggles around and reaches adulthood in three days. “It consists basically of two tubes, one inside the other,” the English biologist John Sulston wrote in a memoir.

Although some colleagues thought he was wasting time, Dr. Sulston for years spent up to eight hours a day peering through microscopes at these worms. His findings on the genetics of worms won him a Nobel Prize for physiology in 2002.

. . .

His work didn’t involve “bold theories or sudden leaps of understanding,” he wrote in a 2002 memoir, “The Common Thread.” Instead, he saw his role as “gathering data for the sake of seeing the whole picture.”

For the full obituary, see:

James R. Hagerty. “Exhaustive Study of a Worm Ended in Nobel Prize.” The New York Times (Saturday, March 17, 2018): A9.

(Note: ellipsis added.)

(Note: the online version of the obituary has the date March 16, 2018, and has the title “Sulston’s Work on Lowly Worm Led to Major Role in Mapping Human Genome.”)

Sulston’s 2002 memoir, mentioned above, is:

Sulston, John, and Georgina Ferry. The Common Thread: A Story of Science, Politics, Ethics and the Human Genome. Washington, DC: Joseph Henry Press, 2002.

“Results Are Often Suspiciously Consistent with the Political Dispositions of the Modeler”

(p. 14) For scholars and popular writers alike, the Great Depression has long been a kind of economic Rorschach test. Free marketers look at the economic disaster and blame the Smoot-Hawley tariff, which inaugurated a global trade war; monetarists attack the Federal Reserve for its tight-money policies; Keynesians berate Herbert Hoover for his attempts to balance the budget as the crisis worsened.

. . .

Generally, . . . , Morris is remarkably evenhanded, giving both sides of scholarly debates in deep detail. This is particularly the case in his coverage of the New Deal, where he weighs the practical effects of the dizzying array of policies begun by Roosevelt, from his devaluation of the dollar to the creation of the Civilian Conservation Corps. And Morris explains in accessible prose how economists have used modeling to study the New Deal (he wryly notes that this “is still a work in progress — if only because results are often suspiciously consistent with the political dispositions of the modeler”).

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