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Experts demolish studies suggesting COVID-19 is no worse than flu



Enlarge / A COVID-19 blood test is administered outside of Delmont Medical Care on April 22, 2020 in Franklin Square, New York. The test identifies antibodies to the coronavirus.

Frustrated statisticians and epidemiologists took to social media this week to call out substantial flaws in two widely publicized studies trying to estimate the true spread of COVID-19 in two California counties, Santa Clara and Los Angeles.

The studies suggested that far more people in each of the counties have been infected with the new coronavirus than thought—that is, they estimated that true case counts in the two counties are up to 85 times and 55 times the number of the currently confirmed cases in the counties, respectively. Accordingly, this suggests that COVID-19 is far less deadly than thought. The large case counts in relation to unchanged number of deaths put COVID-19’s fatality rate in the same range as seasonal flu.

How dangerous is this?

We dig into the details of the studies below, but it’s important to note that neither of them have been published in a scientific journal, nor have they gone through standard peer-review for scientific vetting. Instead, they have been posted online in draft form (a commonplace occurrence amid a rapidly evolving pandemic that inclines researchers to have fast access to data, however uncertain).

The findings seemed to support minority arguments that COVID-19 may be no worse than seasonal flu (a leading cause of death in the US) and that the restrictive mitigation efforts currently strangling the economy may be unnecessary. In fact, three researchers who co-authored the new studies have publicly made those exact arguments.

In a controversial opinion piece in the biomedical news outlet STAT, population health researcher John Ioannidis, at Stanford, argued back in mid-March that the mortality rate of COVID-19 may be much lower than expected, potentially making current lockdowns “totally irrational.” Health policy researchers Eran Bendavid and Jay Bhattacharya, also both at Stanford, made a similar argument in The Wall Street Journal at the end of March. They called current COVID-19 fatality estimates—in the range of 2 percent to 4 percent—“deeply flawed.”

Ioannidis is a co-author of the study done in Santa Clara county, and Bendavid and Bhattacharya were leading researchers on both of the studies, which appeared online this month.

The new studies seem to back up the researchers’ earlier arguments. But a chorus of their peers are far from convinced. In fact, criticism of the two studies has woven a damning tapestry of Twitter threads and blog posts pointing out flaws of the studies—everything from basic math errors to alleged statistical sloppiness and sample bias.

In a blog review of the Santa Clara county study, statistician Andrew Gelman of Columbia University detailed several troubling aspects of the statistical analysis. He concluded:

I think the authors of the above-linked paper owe us all an apology. We wasted time and effort discussing this paper whose main selling point was some numbers that were essentially the product of a statistical error.

I’m serious about the apology. Everyone makes mistakes. I don’t think they[sic] authors need to apologize just because they screwed up. I think they need to apologize because these were avoidable screw-ups.

A Twitter account from the lab of Erik van Nimwegen, a computational systems biologist at the University of Basel, responded to the study by tweeting the quip “Loud sobbing reported from under reverend Bayes’ grave stone.” The tweet refers to Thomas Bayes, an 18th-century English reverend and statistician who put forth a foundational theorem on probability.

Pleuni Pennings, an evolutionary biologist at San Francisco State University, noted in a blog regarding the Santa Clara study that “In research, we like to say that ‘extraordinary claims require extraordinary evidence.’ Here the claim is extraordinary but the evidence isn’t. Also, we learn that even if a study comes from a great university—this is no guarantee that the study is good.”

Harvard epidemiologist Marc Lipsitch stated on Twitter that he concurred with similar statistical criticisms made online. He added a “kudos” to the authors for conducting the study and “providing one interpretation of it (which supports their ‘it’s overblown’ view).”

So what has all of these researchers up in arms?

The aim of the studies

Both studies primarily aimed to estimate how many people in each of two counties had been infected at some point with SARS-CoV-2. This is an extremely important endeavor because it can tell us the true extent of infection, help guide efforts trying to stop transmission, and better assess the full spectrum of the COVID-19 disease severity and the fatality rate.

Because diagnostic testing has been so limited in the US and many COVID-19 cases appear to present with mild or even no symptoms, researchers expect the true number of people who have been infected to be much higher than we know based on confirmed cases. There is no debate about that. But just how much higher is the subject of considerable debate.

The researchers went about their studies by recruiting small groups of residents and testing their blood for antibodies against SARS-CoV-2. Antibodies are Y-shaped proteins that the immune system makes to target specific molecular foes, such as viruses. If a person has antibodies that recognize SARS-CoV-2 or its components, that suggests the person was previously infected.

Santa Clara

In the Santa Clara county study, researchers recruited volunteers using Facebook and had them come to one of three drive-through test sites. They ended up testing the blood of 3,330 adults and children for antibodies. They found 50 blood samples, or 1.5 percent, were positive for SARS-CoV-2 antibodies.

They then adjusted their figures to try to estimate what positive tests they would have gotten back if their pool of volunteers better matched the demographics of the county. The volunteer pool skewed toward certain zip codes in the county and were enriched for women and white people relative to the county’s real makeup. The researchers’ adjustment ended up nearly doubling the prevalence of positives, bringing them from 1.5 percent to an estimated 2.8 percent.

They then adjusted the data again to account for inaccuracies of the antibody test. There are two metrics for accuracy here: sensitivity and specificity. Sensitivity relates to how good the test is at correctly identifying all true positives. Specificity relates to how good the test is at correctly identifying all the true negatives—in other words, avoiding false positives.

According to the authors of the Santa Clara study, the sensitivity and specificity data on their antibody test led them to estimate that the true prevalence of SARS-CoV-2 infections ranged from 2.49 percent and 4.16 percent.

Based on the population of the county, that would suggest somewhere between 48,000 and 81,000 people in the county had been infected. The confirmed case count at the time of publication was only 956. That puts their infection estimate 50 to 85 times higher than the confirmed cases.

The researchers then estimated an infection fatality rate (IFR) with that large number of estimated infections and an estimate of only 100 cumulative deaths (including from infections at the time. Deaths lag behind initial infections, potentially for weeks). They calculated an IFR of 0.12 percent to 0.2 percent. This falls in the ballpark of seasonal flu, which has an estimated fatality rate of about 0.1 percent.

Los Angeles

There is less data available from the Los Angeles study. In an unusual move—even by today’s pandemic standards—the findings were initially announced in a press release from the county’s public health department, which provided little in the way of statistical and methodological details. A short draft of the study (PDF found here) has also circulated online, but it still has less information on the methods than the Santa Clara study. Also, the draft has even higher prevalence estimates than the press release. It’s unclear why the estimates differ, but we’ll mainly focus on the conclusions formally released from the health department.

Generally, for the study, researchers used data from a market research firm to randomly select residents and invite them to get tested at one of six testing sites. The researchers set up quotas for participants by age, gender, race, and ethnicity to match the population characteristics of the county. Their goal was to recruit 1,000 participants.

They tested 863 adults using the same antibody test used in the Santa Clara study, which was made by Premier Biotech, of Minneapolis, Minnesota. Of the tests given, 35 (or 4.1 percent) were positive. According to the press release, the adjusted data suggested that 2.8 percent to 5.6 percent of the county’s population had been infected with the new coronavirus.

Given the county’s population, that suggests that 221,000 to 442,000 adults in the county had been infected. That estimate is 28- to 55-times higher than the 7,994 confirmed case count at the time. As in the Santa Clara study, that puts the IFR in the range of 0.3 percent to 0.13 percent, closer to the IFR of seasonal flu.

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Prescription poop is here: FDA approves fecal slurry for unshakeable diarrhea



Enlarge / Laboratory technicians in France prepare stool to treat patients with serious colon infections by fecal microbiota transplantation (FMT), also known as gut flora transplant (GFT) in 2019.

For the first time, the US Food and Drug Administration has granted approval for a feces-based microbial treatment, which is used to prevent a recurring diarrheal infection that can become life-threatening.

The approval, announced Wednesday, is years in the making. Researchers have strained to harness the protective qualities of the complex, diverse, yet variable microbial communities found in healthy people’s intestines and stool. Early on, rich fecal matter proved useful for restoring balance and blocking infection in those whose microbiomes have been disturbed—a state called dysbiosis, which can occur from disease and/or use of antibiotic drugs. But, our understanding of what makes a microbiome healthy, functional, and protective remains incomplete.

Doctors, meanwhile, pushed ahead, informally trying an array of methods to transplant fecal microbiota from healthy donors to the guts of patients—via enemas, tubes through the nose, and oral poop-packed capsules. Fecal microbiota transplants (FMTs) have been used to treat various ailments, from obesity to irritable bowel syndrome, to mixed success. But it quickly became apparent that FMTs were most readily effective at preventing recurrent infection from Clostridioides difficile (C. difficile or just C. diff).

C. diff bacteria cause diarrhea and significant inflammation in the colon. Severe infections can be life-threatening. In people with dysbiosis, C. diff can proliferate in the intestines, producing toxins that can lead to organ failure. Older people, those who are hospitalized, and people with weakened immune systems are particularly susceptible to C. diff, which can recur over and over in some vulnerable patients. In the US, C. diff infections are associated with up to 30,000 deaths per year.

With the pressing need for effective treatments against C. diff, regulators were forced to wade through the mucky issue of regulating and standardizing something as unruly and myriad as fecal matter. It also led to years of microbial sleuthing, synthetic slurries, stool donations, and clinical trials.

Solid success

Now, a product has finally floated to the top: Rebyota, a blend of donor stool, saline, and laxative solution given in a single treatment as an enema. It’s teeming with heavily screened intestinal microbes at a concentration of 10,000,000 live organisms per milliliter. Its owner, Switzerland-based Ferring Pharmaceuticals, screens donors and their donated stool for a long list of infectious pathogens and other health factors.

In a Phase III clinical trial involving 262 participants—the results of which were published last month—Ferring’s scientists reported that treatment with Rebyota led to a higher prevention rate of recurrent C. diff infections than in a placebo group at a rate of 70.6 percent in the treatment group compared with 57.5 percent in the placebo group. Prevention of C. diff was defined as an absence of C. diff diarrhea for eight weeks following treatment or placebo. The treatment was well tolerated, with no serious side effects. The FDA noted that given the variability of fecal matter, there is a potential that it could contain an unforeseen infectious agent or food allergens.

The approval of Rebyota is “an advance in caring for patients who have recurrent C. difficile infection,” Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, said in an announcement. “Recurrent CDI impacts an individual’s quality of life and can also potentially be life-threatening. As the first FDA-approved fecal microbiota product, today’s action represents an important milestone, as it provides an additional approved option to prevent recurrent CDI.”

Ferring—which acquired Rebyota in 2018 when it purchased its developer Minnestoa-based Rebiotix—also celebrated the approval.

“We believe this is a major breakthrough in harnessing the power of the human microbiome to address significant unmet medical needs. This is the first FDA approval of a live biotherapeutic and the culmination of decades of research and clinical development,” Ferring president Per Falk said. “Today’s announcement is not just a milestone for people living with recurrent C. difficile infection, but also represents a significant step which holds promise that many other diseases might be better understood, diagnosed, prevented, and treated using our rapidly evolving insights on the role of the microbiome in human health and disease.”

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Over a year later, Musk’s Neuralink still 6 months from human trials



Enlarge / The on-stage demo of the surgical robot practically extended into the audience.

On Wednesday night, Elon Musk hosted an update from his brain-computer interface company, Neuralink. Most of the update involved various researchers at the company providing overviews of the specific areas of technology development they were working on. But there wasn’t anything dramatically new in the tech compared to last year’s update, and it was difficult to piece the presentations together into a coherent picture of what the company plans to do with its hardware.

But probably the most striking thing is that last year’s update indicated that Neuralink was getting close to human testing. Over a year later, those tests remain about six months out, according to Musk.

Lots of tech

Neuralink involves a large series of overlapping technical efforts. The interface itself requires electrodes implanted into the brain. To connect those electrodes with the outside world, Neuralink is using a small bit of hardware implanted in the skull. This contains a battery that can be recharged wirelessly, and a low-power chip that gathers data from the electrodes, performs some simple processing on it, and then transmits that data wirelessly.

Getting all that in place requires delicate neurosurgery, and the company is developing a surgical robot to make that process safe and consistent.

On the other end of the process, neural signals have to be interpreted in near real time to understand what’s happening in a given brain region. This requires computer systems that can handle everything from patient-to-patient variability to hour-to-hour differences in brain activity. Finally, in some cases, the device will need to send information back to the brain in a way that the nerve cells there can interpret (either immediately or following a learning process).

That’s… a lot of things. And the event saw people talking about almost all of them. In many cases, the information was substantially similar to what was shown the year before. Various animals with implants were shown doing everything from playing Pong to manipulating cursors and typing using their implants—more examples than last year, but not radically different. Similarly, Musk talked a bit more about the implant’s processing capacity, now provided partly by an ARM processor. There are some indications of evolutionary progress, but there are no indications that it’s close to a finalized design that’s ready for a Food and Drug Administration submission.

Perhaps the most significant difference from years prior is the level of detail involved in the surgical robot. This time, there was both an on-stage demo of the hardware and a fair bit of time spent discussing the details of the surgical procedure it was being developed for. In the previous update, the development of the robot appeared to be lagging.

We’ve been here before

The event was said to be a general overview of the company’s activities, and the presentations seemed to cover all of the key areas Neuralink is working on. But there are issues with that approach.

One is that brain implants have been an active research area for decades. While the details are different, many things Neuralink was showing off have been done before. To an extent, that’s understandable. Neuralink is developing its own electrodes, implant, and processing system. As such, it needs to demonstrate that these systems can perform like previously tested electrodes in animal experiments. But, so far, at least, Neuralink hasn’t provided any indications that its systems are superior to those that have already been tested extensively or were on a trajectory to get there.

Meanwhile, some of its competitors progressed in the areas where Neuralink sought to differentiate itself. Blackrock Neurotech, for example, is now touting fully implantable electronics that offer wireless charging and data transfer. And the company has already sent hardware through a clinical trial and is applying for FDA approval. In fact, the company has several additional clinical trials in progress.

The custom surgical robot seems unique to Neuralink (though surgical robots are widely used for other purposes). But one of the Neuralink staff mentioned that the robot was a sticking point with the FDA, saying it’s difficult to demonstrate its safety to the satisfaction of regulators. And another one of its competitors, Synchron, hopes to avoid the need for major surgery by using blood vessels to get implants deep into the brain. And those devices have also managed to go through clinical trials already.

Another problem with Neuralink’s progress update is that it doesn’t clearly indicate that the company is ready to go to the FDA. Starting a clinical trial will mean that the company has finalized a hardware design (even if it’s working on next-generation hardware separately) and chosen a specific neural defect that it plans to treat. The update’s scattershot progress reports gave no indication that any of that has been done.

None of this is to say that there won’t ultimately be space for multiple technologies in the brain-computer implant space. Neuralink will likely eventually arrive where some of these other companies are now, or it might find a niche where its hardware is especially effective. But so far, the company isn’t sharing any information that indicates that it’s close to either result—much less accomplishing some of the more outlandish claims thrown around by Musk.

Neuralink’s presentation is available online. Oddly, for an organization run by a self-professed fan of free speech, the company has disabled comments on the video.

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A new satellite has become one of the 20 brightest stars in the sky



Enlarge / Observation of a BlueWalker 3 pass from Oukaimeden Observatory on Nov. 16 2022. The bright star lower left is Zeta Puppis.

CLEOsat/Oukaimeden Observatory/IAU CPS/A.E. Kaeouach

Last month, a Texas-based company announced that it had successfully deployed the largest-ever commercial communications satellite in low-Earth orbit.

This BlueWalker 3 demonstration satellite measures nearly 65 square meters, or about one-third the size of a tennis court. Designed and developed by AST SpaceMobile, the expansive BlueWalker 3 satellite is intended to demonstrate the ability of standard mobile phones to directly connect to the Internet via satellite. Large satellites are necessary to connect to mobile devices without a ground-based antenna.

In this emerging field of direct-to-mobile connectivity, which seeks to provide Internet service beyond the reach of terrestrial cellular towers, AST is competing with Lync, another company that also has launched demonstration satellites. In addition, larger players such as Apple and a team at SpaceX and T-Mobile have announced their intent to provide direct connectivity services.

So while there are many more such satellites coming, AST stands out at this time because it’s the first to launch an exceptionally large satellite, and it plans to start launching operational “BlueBird” satellites in late 2023.

IAU concerns

Since BlueWalker3’s launch in September, astronomers have been tracking the satellite, and their alarm was heightened following its antenna deployment last month. According to the International Astronomical Union, post-deployment measurements showed that BlueWalker 3 had an apparent visual magnitude of around 1 at its brightest, which is nearly as bright as Antares and Spica, the 15th and 16th brightest stars in the night sky.

For a few years, astronomers have been expressing concerns about megaconstellations, such as SpaceX’s Starlink satellites. While these are more numerous—there are more than 3,000 Starlink satellites in orbit—they are much smaller and far less bright than the kinds of satellites AST plans to launch. Eventually, AST plans to launch a constellation of 168 large satellites to provide “substantial” global coverage, a company spokesperson said.

Even one is enough for astronomers, however. “BlueWalker 3 is a big shift in the constellation satellite issue and should give us all reason to pause,” said Piero Benvenuti, a director at the International Astronomical Union.

The organization of astronomers is also concerned about the potential for radio interference from these “cell phone towers in space.” They will transmit strong radio waves at frequencies currently reserved for terrestrial cell phone communications but are not subject to the same radio quiet zone restrictions that ground-based cellular networks are. This could severely impact radio astronomy research—which was used to discover cosmic microwave background radiation, for example—as well as work in related fields.

Astronomers currently build their radio astronomy observatories in remote areas, far from cell tower interference. They are worried that these large, radio-wave transmitting satellites will interfere in unpopulated areas.

AST responds

An AST spokesperson provided a statement to Ars that said the impact of its satellites must be weighed against the “universal good” of cellular broadband for people on Earth. However, the company also said it is willing to work with astronomers to address their concerns.

“We are eager to use the newest technologies and strategies to mitigate possible impacts to astronomy,” the AST statement said. “We are actively working with industry experts on the latest innovations, including next-generation anti-reflective materials. We are also engaged with NASA and certain working groups within the astronomy community to participate in advanced industry solutions, including potential operational interventions.”

To that end, AST said it is committed to avoiding broadcasts inside or adjacent to the National Radio Quiet Zone in the United States, which is a large area of land that includes portions of West Virginia and Virginia, as well as additional radioastronomy locations.

A US-based astronomer who focuses on light pollution, John Barentine, told Ars he welcomed the company’s efforts to address radio interference. He also appreciates any efforts to mitigate effects on optical astronomy. However, Barentine warned, there is no recourse for astronomers but to take AST and other companies at face value due to a lack of regulatory oversight.

“Overtures by commercial space operators who commit that their activities in space will not adversely affect astronomy are made in the absence of any meaningful regulatory oversight that mandates mitigations,” he said. “AST SpaceMobile’s stated intentions are laudable, but for now, they’re just words. So I reserve judgment pending whatever actions the company takes.”

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