RARE Daily

Sometimes a French Press Is the Best Choice

August 13, 2020

There is a sense that many people have that advanced genome sequencing will become a routine test performed on newborns. A new study in the journal Nature Medicine suggests for now, older, simpler technology may be the best approach.

Researchers at the University of California, San Francisco; The University of California, Berkeley; and Tata Consultancy Services compared how the use of tandem mass spectrometry compares to whole exome sequencing for newborn screening. Tandem mass spectrometry is what California uses to analyze the blood spots taken at birth from newborns to test for rare metabolic disorders.

There has been excitement about the potential to use whole genome sequencing to diagnose newborns who are in the neonatal intensive care unit. Rady Children’s Institute for Genomic Medicine completed a two-year pilot project with the state of California earlier this year that showed its use of rapid whole genome sequencing in real world hospital neonatal and pediatric intensive care units can not only improve outcomes, but also save money.

Rady, though, used advanced technology to test children who were already known to be ill. In this new study, the researchers wanted to see whether whole exome sequencing—which examines the protein coding regions in a genome—provide a better method of newborn screening than conventional testing used in California to detect children with inborn errors of metabolism.

The study, the first to make a comprehensive assessment of how sequencing compares to conventional screening technology, found whole exome screening fell short of the mark. It failed to identify some infants who had rare conditions while identifying some healthy babies for follow-up testing that wasn’t needed.

“There has been a lot of publicity about universal sequencing for newborns,” said Jennifer Puck, professor of pediatrics at UC San Francisco and co-senior author of the study. “But claims that sequencing is the key to health have been made without the support of rigorous studies.”

The researchers used archived residual dried blood spots and data for nearly all cases of inborn errors of metabolism from 4.5 million infants born in California between mid-2005 and 2013. Some of the infants who tested positive by tandem mass spectrometry were found to be unaffected by follow-up testing.

The researchers looked for mutations in 78 genes known to be involved in 48 metabolic disorders using whole exome sequencing. Every newborn in California is screened for these conditions at birth. They are rare conditions that affect about 150 of the estimated half a million babies born each year in California.

The study found whole exome sequencing was not sensitive or specific enough to serve as a primary screen for newborn screening for these metabolic conditions. The researchers, however, said as a secondary test for infants with abnormal screens, the use of whole exome screening could reduce false-positive results, facilitate timely case resolution, and in some cases provide a better diagnosis than that initially obtained.

Puck notes that screening newborns who appear healthy is different from using sequencing as a diagnostic tool for a medical problem that has already been detected.

“All of the prior studies of the utility of exome sequencing have started with a patient already in front of a doctor—in other words, a patient with a problem,” Puck said. “You start with a clue in hand, a person with a particular difficulty, and you’re trying to see if there’s an underlying genetic reason for that. When you switch to screening mode, you don’t have any clues. Most newborns look perfectly healthy.”

Many years ago, I interviewed the then-CEO of Peet’s Coffee. He had given me a tour of the company’s roasting facility in Emeryville, California. After the tour we passed through a small kitchen area where he stopped to make a cup of coffee. He walked past a shiny and elaborate, state-of-the-art coffee machine that occupied a fair bit of real estate on a small counter. It had an industrial beauty and must have cost thousands of dollars. He walked by it and picked up a small, $30 French press to make himself some coffee. When I asked him why he used the French press, he said it made the most flavorful cup of coffee.

Technology can be seductive. I still imagine a time when infants will be routinely sequenced at birth, although we will need to improve costs and our ability to interpret results before that happens. But sometimes, simple is better.

Stay Connected

Sign up for updates straight to your inbox.