Insights & Outcomes: Clinical trial data gaps and a universe of old milk
This month, Insights & Outcomes dissects the demographics of clinical trials for new cancer drugs, gets real about childhood obesity, dives into ancient oceans to learn about the carbon cycle, and draws a parallel between the density of the universe and spoiled milk.
Got cosmic milk?
Ever feel like the universe is just a big carton of old milk? Well, you may be correct.
In a new study in the journal Physical Review Letters, Farnik Nikakhtar, a postdoctoral fellow in Yale’s Department of Physics, theorizes that, ever-so-slowly, the universe has become filled with lumpy clumps of matter. “Initially smooth and uniform with very tiny density fluctuations, Nikakhtar said, “the universe became clumpier over time as gravity pulled more matter into denser regions.”
Nikakhtar and his co-authors — Ravi K. Sheth of the University of Pennsylvania, Bruno Lévy of Centre Inria de Paris, and Roya Mohayaee of Institut d’Astrophysique de Paris and the University of Oxford — developed an “assumption-free” algorithm to model the universe’s initial density. The algorithm is based on the mathematical concept of “Optimal Transport Theory,” which seeks to understand the most efficient way of moving objects from one place to another.
“Optimal Transport is very well-suited to the problem of reconstructing the universe’s initial density field,” Nikakhtar said. “This method also opens up new possibilities for measuring cosmological parameters.”
At Yale, Nikakhtar is working with associate professor of physics and astronomy Nikhil Padmanabhan to apply the new algorithm to observations from the Dark Energy Spectroscopic Instrument (DESI), a cosmological survey that will map 40 million galaxies and quasars.
Bright bodies, bright futures
A third of U.S. children have been found to be either overweight or obese. Though clinical trials have shown some interventions for childhood obesity to be effective, how these interventions might fare in the real world, outside of controlled trial settings, is less clear.
In a new study published in the journal Obesity, Yale researchers assessed the actual effects of Bright Bodies, a Yale program for children ages 7 to 16 that incorporates family-based nutrition education classes, behavior modification classes, supervised physical activity, and parent groups. In 2007, a trial showed that participation in Bright Bodies — developed and directed by nutritionist Mary Savoye — reduced children’s body mass index scores and their risk for diabetes.
In the new study, the researchers found that body mass index scores and body fat percentages for children participating in the Bright Bodies beginner-level program between 2008 and 2018 in fact decreased at a rate comparable to the original trial.
“We now have over a decade of evidence showing the Bright Bodies healthy lifestyle program is effective in a real-world setting,” said Stephanie Samuels, an associate research scientist in the Department of Pediatrics at Yale School of Medicine and lead author of the study.
“This information is timely given the new clinical practice guidelines from the American Academy of Pediatrics,” said Mona Sharifi, associate professor of pediatrics, senior author of the study, and co-author of the new guidelines. “They speak to the need to expand access to evidence-based interventions like Bright Bodies.”
Clinical trial demographics by the numbers
Despite widespread agreement that clinical trials should enroll a representative sampling of individuals from different age, gender, and racial and ethnic groups, a new Yale School of Medicine study shows that clinical trials on new cancer drugs still fall far short of including key data on several demographic groups. The findings were published in the journal BMJ Medicine.
For the study, the Yale team — led by Jennifer Miller, associate professor of medicine and senior author, and Tanvee Varma, a fourth-year medical student and lead author — developed a series of quality control metrics to assess how well pharmaceutical companies reported on and included demographic groups in cancer trials, conducted between 2012 and 2017, that led to U.S. Food and Drug Administration approval of new drugs.
Of the 24 companies submitting key trial results, all but one failed to publicly report at least some demographic data on participants, the researchers found. Although all of the companies reported participants’ sex, more than 60% failed to report age and almost 80% did not report race and ethnicity data.
Half of the companies also failed to adequately represent women in at least one trial supporting their product approvals. About 75% of companies did not adequately represent older adults and more than 4 out of 5 did not adequately represent patients identifying as Black or Latinx.
“We created a baseline scorecard for companies to spur a race to the top in reporting and including under-represented groups in clinical trials,” Miller said.
The importance of including diverse populations in drug and treatment trials has been known for decades; people can respond differently to diagnostic tests or treatments depending upon their sex, age, or racial background, which can affect the quality of treatment they receive.
“While a few companies have done well in meeting diversity standards, most have substantial room for improving their fair inclusion of older adults and racial and ethnic minoritized patients, and to a lesser extent women, in cancer pivotal trials,” Miller said. “We still need to move the needle.”
The study was funded by the Susan G. Komen Foundation.
Grand opening for a marine carbonate factory
The rise of marine animals hundreds of millions of years ago had far-reaching implications for the eventual diversity of life on Earth. It also permanently changed the way the oceans store carbon.
In a new study published in the journal Nature, researchers found that at the same time the world’s oceans began to fill with animals with carbonate shells and skeletons, a major shift occurred in how carbonates formed in seawater. Suddenly — and permanently — the oceans were less readily able to precipitate carbonate minerals, or limestone.
The formation of carbonate minerals from dissolved chemicals in seawater allows, over millions of years, for the near-permanent storage of carbon dioxide from the atmosphere.
“We used a mixture of novel geochemical methods and information from sedimentary databases to analyze rocks spanning the entirety of Earth's history,” said Lidya Tarhan, an assistant professor of Earth and planetary sciences in Yale’s Faculty of Arts and Sciences, and co-corresponding author of the study.
Jiuyuan Wang, an Agouron Geobiology Postdoctoral Fellow in Tarhan’s lab, is first author and co-corresponding author. Co-authors are Noah Planavsky, a Yale professor of Earth and planetary sciences, Andrew Jacobson of Northwestern University, and Amanda Oehlert of the University of Miami.
The researchers also found evidence that a major share of marine carbonates was buried in the deep oceans during Earth’s early history, in contrast to the long-held notion that marine carbonates formed only in shallow waters until the much more recent emergence of calcifying plankton.