Category: Methodology

Hydroxychloroquine Clinical Trials Suspended on Basis of Lancet Article Containing “Major Inconsistencies”

(p. A11) A group of scientists who raised questions last week about a study in The Lancet about the use of antimalarial drugs in coronavirus patients have now objected to another paper about blood pressure medicines in the New England Journal of Medicine, which was published by some of the same authors and relied on the same data registry.

Moments after their open letter was posted online Tuesday morning [June 2, 2020], the editors of the N.E.J.M. posted an “expression of concern” about the paper, and said they had asked the paper’s authors to provide evidence that the data are reliable.

The Lancet followed later in the day with a statement about its own concerns regarding the malarial drugs paper, saying that the editors have commissioned an independent audit of the data.

. . .

In their letter to the N.E.J.M., critics of the work wrote: “Serious, and as yet unanswered, concerns have been raised about the integrity and provenance of these data.”

The letter points out “major inconsistencies” between the number of coronavirus cases recorded in some countries during the study period and the number of patient outcomes reported by the researchers over the same period.

. . .

Many of the scientists who first raised concerns about the database are involved in clinical trials of chloroquine and hydroxychloroquine, and they were forced to pause the studies for safety reviews after The Lancet study was published.

James Watson, a senior scientist with MORU Tropical Health Network, said his unit had to immediately suspend work on a large randomized clinical trial to see if chloroquine or hydroxychloroquine can protect health care workers exposed on the job to the coronavirus from infection.

“I saw very quickly this paper didn’t hold up to much scrutiny at all,” he said. “We started wondering, ‘Who’s been collecting this data, and where did it come from?’ We were quite surprised to see a global study with only four authors listed and no acknowledgment of anyone else.”

. . .

David Glidden, a professor of biostatistics at University of California, San Francisco, who reads all new publications about Covid-19 antiviral therapies as a member of a National Institutes of Health clinical guidelines panel, said he was immediately struck by the vagueness of the descriptions in both papers.

For the full story, see:

Roni Caryn Rabin. “Scientists Question Medical Data From Single Company Used in Two Studies.” The New York Times (Wednesday, June 3, 2020): A11.

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

(Note: the online version of the article was updated June 2, 2020, and had the title “Scientists Question Medical Data Used in Second Coronavirus Study.”)

Trump Walks the Walk on Hydroxychloroquine

(p. A6) WASHINGTON—President Trump said he is taking hydroxychloroquine, an antimalarial drug that he has cited as a possible defense against the novel coronavirus but that some scientists have cautioned needs further study and could be dangerous.

“I happen to be taking it, hydroxychloroquine,” he told reporters at the White House on Monday. He said he had consulted with the White House doctor and suggested he is taking the drug as a preventive measure. Mr. Trump said he has been checked regularly for Covid-19, has tested negative and has no symptoms. He said he has been taking hydroxychloroquine for about a week and a half.

. . .

On Monday [May 18, 2020], Mr. Trump continued to stress anecdotal evidence in favor of the drug and told reporters, “I was just waiting to see your eyes light up when I said this.” He also expressed confidence in the drug’s safety. “I’m not going to get hurt by it. It’s been around for 40 years for malaria, for lupus, for other things.”

For the full story, see:

Catherine Lucey, Jared S. Hopkins. “President Trump Says He Is Taking Hydroxychloroquine as Preventive.” The Wall Street Journal (Tuesday, May 19, 2020): A6.

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

(Note: the online version of the story has the date May 18, 2020, and has the title “Trump Says He Takes Contested Drug for Prevention.”)

The key reference on advocates of a drug who take it first themselves, without confirmation from randomized double-blind clinical trials, is:

Altman, Lawrence K. Who Goes First?: The Story of Self-Experimentation in Medicine. Berkeley, CA: University of California Press, 1998.

Physicians Fighting Covid-19 Use Social Media “to Share Improvised Solutions”

(p. A9) In mid-March [2020], as U.S. hospitals scrambled for ventilators to treat a surge of coronavirus cases, a Vermont pulmonologist proposed a different treatment on a blog popular with emergency-medicine doctors.

Joshua Farkas observed in the post on the EMCrit blog that many Covid-19 patients seemed to benefit from less-invasive alternatives to help their breathing, including pressure therapy used to treat sleep apnea—sometimes referred to as CPAP, for continuous positive airway pressure.

. . .

The post helped galvanize an emerging theory about the treatment of Covid-19 patients, which in recent weeks has taken hold in U.S. hospitals. In New York City, where ventilators are in perilously short supply, doctors say they have since embraced CPAP and other treatments to improve breathing in Covid-19 patients.

The shift is one example of how health-care workers are writing the playbook for treating coronavirus patients on the fly, knowing they can’t wait for peer-reviewed articles or studies in established medical journals. Instead they are tapping into social media, podcasts, inside-baseball medical blogs and text-message groups to share improvised solutions to supply shortages and patient care, forcing hospitals to quickly re-evaluate their practices.

“This has been a rapidly evolving process,” said Dr. Farkas, who has treated Covid-19 patients in the intensive-care unit at the University of Vermont in Burlington. “As we struggle with how to treat a disease that so recently was totally unknown, this rapid exchange and updating of information is crucial.”

. . .

Last week, Michelle Romeo, a chief emergency-medicine resident at NYU Langone and Bellevue hospital in Manhattan, tweeted photos of a jury-rigged breathing device involving a mask used for BiPAP—an airway pressure therapy similar to CPAP.

At Mount Sinai Hospital in Manhattan, pulmonologists worked with the hospital’s sleep lab to figure out a way to use BiPAP machines like a ventilator. The result was posted on Reddit, and got “all kinds of different responses,” said Valerie Burgos-Kneeland, a registered nurse in the hospital’s Medical Intensive Care Unit. “It’s kind of been an opportunity for people to get creative.”

For the full story, see:

Rebecca Davis O’Brien. “Doctors Improvise, Share Treatments.” The Wall Street Journal (Friday, April 10, 2020): A9.

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

(Note: the online version of the story has the date April 9, 2020, and has the title “Doctors Are Improvising Coronavirus Treatments, Then Quickly Sharing Them.”)

“Real World Evidence” on Effectiveness of Experimental Drugs Can Be Extracted From Electronic Health Records

(p. A7) . . . analysis of compassionate-use data, about the experimental drug remdesivir from Gilead Sciences Inc. published in the New England Journal of Medicine, came under criticism. Scientists pointed out that the Covid-19 patients received the drug in centers around the world where care may have differed, data on some patients was incomplete and there was no comparison group.

That study’s first author, Jonathan Grein, of Cedars-Sinai Medical Center in Los Angeles, said given how little is known about the coronavirus and how to treat it, “I think at this point any information is potentially helpful.” He said the study, funded by Gilead Sciences, noted the findings were limited and preliminary. “It is a starting point, an opportunity to aggregate our initial experiences,” he said.

. . .

The FDA . . . has worked closely with companies trying to extract “real world evidence” about patients’ experiences with new or experimental drugs from sources such as electronic health records.

For the full story, see:

Amy Dockser Marcus. “Hundreds Get Plasma in National Study.” The Wall Street Journal (Wednesday, April 22, 2020): A7.

(Note: ellipses added.)

(Note: the online version of the story has the date April 21, 2020, and has the title “Hundreds Receive Plasma From Recovered Coronavirus Patients in National Study.”)

Early Promising Results from Gilead-Sponsored Study on Remdesivir

(p. B3) A doctor in Chicago told colleagues that Gilead’s drug remdesivir appeared to help many patients enrolled in a clinical trial site at the University of Chicago Medicine hospital, according to a news report in online health publication STAT, which cited a video of the remarks. The doctor said that the hospital had enrolled 125 patients in two remdesivir studies sponsored by Gilead, and that most had been discharged from the hospital, and two had died.

. . .

“Partial data from an ongoing clinical trial is by definition incomplete and should never be used to draw conclusions about the safety or efficacy of a potential treatment that is under investigation,” a University of Chicago spokeswoman said in an email. “Drawing any conclusions at this point is premature and scientifically unsound.”

. . .

Last week, Gilead reported in the New England Journal of Medicine that remdesivir showed encouraging results in treating 53 patients with severe Covid-19 symptoms. The patients were given the drug under so-called compassionate use, which allows for doctors to request unapproved drugs for patients in emergency situations.

Of the 53 compassionate use patients who received remdesivir, nearly half were discharged from the hospital and seven patients died, or 13% of the total, according to the New England Journal paper. Of 30 patients using breathing tubes connected to ventilators, 17 had their tubes disconnected after remdesivir treatment.

For the full story, see:

Joseph Walker. “Gilead Shares Up 9.7% On Encouraging Signs In Covid-19 Drug Trial.” The Wall Street Journal (Saturday, April 18, 2020): B3.

(Note: ellipses added.)

(Note: the online version of the story has the date April 17, 2020, and has the title “Coronavirus Drug Report, Though Inconclusive, Sends Gilead Higher.” Where the versions differ, the passages quoted above follow the somewhat longer online version.)

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.”)