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Newborn Sequencing Study Leaders Grapple With Factors Limiting Uptake

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NEW YORK (GenomeWeb) – It may be trickier than expected to entice new parents to have their babies sequenced, though the full suite of reasons for this hesitation — along with the most appropriate timing and circumstances for discussing sequencing with parents — are still being unraveled.

Brigham and Women's Hospital geneticist Robert Green made headlines a couple of weeks ago when he presented data at the American Society of Human Genetics annual meeting in Vancouver, Canada suggesting fewer than 7 percent of couples approached for the BabySeq project consented to having their healthy newborns or newborns in the neonatal intensive care unit (NICU) considered for sequencing.

The BabySeq study is being done with an eye to a future when genomics is a routine part of medical practice and preventative medicine, Green said. As the technology becomes more common, researchers are attempting to parse out some of the clinical, personal, societal, ethical, and legal implications of having access to information in an infant's exome or genome.

But are parents of healthy newborns really interested in having their newborns sequenced? If so, just how much time and effort are they willing to invest? And if not, what are the main deterrents? 

In late 2014, Green's team published findings from a pilot study in Genetics in Medicine indicating that almost 83 percent of the 514 parents questioned in the hospital within 48 hours of their baby's birth were "somewhat," "very," or "extremely" interested in newborn genomic testing.

That level of enthusiasm hasn't translated into enrollment during the main phase of the project, at least so far. Among parents of the first 2,062 healthy newborns born at Brigham and Women's Hospital since the study started, just 229 attended a pre-enrollment session for BabySeq and 138 — or 6.7 percent — went on to reach full enrollment, sign the consent form, and complete a baseline survey.

Perhaps more surprisingly, the parents of infants in the NICU appear just as hesitant to join the BabySeq study, despite the possibility of uncovering genetic contributors to their child's condition. There, 24 infants were fully enrolled from the 345 families approached, and 47 reached the pre-enrollment stage. So far, the team has provided reports for 45 healthy infants and six infants in the NICU.

Among parents who opted against participating in the study before the pre-enrollment discussion, logistics such as paperwork and return visits to the hospital were most often described as deterrents — perhaps not surprising for busy families focusing on their baby's arrival. On the other hand, parents who opted against participating after the pre-enrollment session mainly mentioned concerns about confidentiality, privacy, genetic discrimination, and insurance coverage.

Green noted that part of the discrepancy between interest reported previously and that observed in the main study may come down to the stage at which parents are considered to have accepted or declined sequencing: while parental interest for the pilot study was gauged in parents interested enough to hear more about the research, the tally for the main BabySeq study includes parents who closed the door to sequencing straightaway when approached in the hospital room with their newborn.

There have also been a few instances where one parent is interested in sequencing and the other is not, he said. Both parents must consent to sequencing before a newborn can participate in BabySeq — an important consideration when information in the baby's genetic code might unwittingly uncover clinical clues relevant to his or her parents.

BabySeq investigators are only returning information related to actionable mutations in genes related to childhood onset conditions. Even so, the Brigham and Women's Hospital did seek and obtain IRB approval to return results related to a BRCA2 mutation detected in one of the healthy sequenced newborns, which was medically relevant to the baby's mother and her family.

Just two of the National Institutes of Health's "Newborn Sequencing in Genomic Medicine and Public Health" (NSIGHT) projects — BabySeq and the NC NEXUS project led by investigators at the University of North Carolina at Chapel Hill — are returning results for healthy infants and, consequently, require consent from parents of children with no known health problems.

The BabySeq researchers are currently enrolling two groups of infants: 240 healthy newborns from Brigham and Women's Hospital and as many infants from the neonatal intensive care unit at Boston Children's Hospital. In each arm of the study, infants are randomized into two groups: one gets a genome report along with standard newborn screening and a family history, and the other does not.

A genome report detailing risk and carrier status related to childhood diseases gleaned from exome sequencing data is returned to doctors caring for the healthy infants, while the NICU baby genome report also contains relevant pharmacogenomic information, if any, and may include variants suspected of contributing to the infants' condition.

For the NC NEXUS study at UNC Chapel Hill, meanwhile, investigators intend to profile 400 infants, including 200 infants with known genetic disorders picked up through standard newborn screening such as congenital hearing loss or phenylketonuria.

Exome sequencing will be randomized for another group of 200 healthy infants as well. There, though, the team is attempting to recruit as many parents of healthy infants as possible during the prenatal period — theoretically giving them lots of time to go over consent information and genetic considerations before their baby arrives. These parents are typically approached at UNC's prenatal-Ob/Gyn clinic when they come in for an ultrasound at around 16 or 18 weeks of pregnancy.

"We don't recruit until the second trimester, but I think a lot of the families are thinking, 'We've got all this time,' but we're trying to get them to finish up the different steps because we know how hectic things can get around the time of the birth," said NC NEXUS leader Cynthia Powell, a genetics and pediatrics researcher at UNC Chapel Hill, noting that there are online surveys accompanying the study and an online decision-aid tool that both parents complete together.

Since recruiting for NC NEXUS started in April of this year, the team has a 30 percent rate of enrollment for parents of infants with a known genetic risk. So far just one baby has been born in the healthy arm of the study, Powell noted, though dozens more couples who have babies due early next year have expressed interest or are in the process of enrolling.

Researchers involved in that study plan to give some parents of healthy infants the option of genomic results related not only to childhood-onset conditions, but also medically actionable mutations associated with diseases that can strike later in life such as mutations in BRCA1 or BRCA2 that have been implicated in breast and ovarian cancer risk.

Powell explained that her team is not looking at critically ill newborns, which have been the focus of the newborn sequencing study at centers such as Children's Mercy Hospital in Kansas City. 

Stephen Kingsmore, who was instrumental in establishing the rapid genome sequencing protocol used for the Children's Mercy Hospital newborn sequencing study, has since moved to Rady Children's Hospital in San Diego. He has outlined plans to use a similar STAT-seq protocol to sequence infants from a level IV NICU at that center.

In contrast, an NSIGHT project at the University of California at San Francisco called NBSeq is using around 1,700 de-identified blood spots to compare metabolic patterns predicted by exome sequencing with those detected by direct mass spectrometry-based metabolic testing.

"We are doing exome sequencing without linking to the individual people," NBSeq leader Jennifer Puck, a pediatrics researcher at the University of California at San Francisco, said. "We never go back to the person, so there is no consent issue."

Another arm of NBSeq does require enrollment and consent. That work involves retrospective exome sequencing on archived blood spot samples for up to 50 children or young adults referred from a center specialized in dealing with immunology-related health conditions. The goal there is to try to understand whether conditions that appeared later in the individuals' lives might have been predicted by exome sequencing on their newborn blood samples.

"We're not having any trouble enrolling people to participate in this," Puck said, "because this could be a way that they could learn what exactly is wrong with their immune system from a genetic point of view."

Since the exomes produced for that study are research quality, that team does not return results to families. Rather, when the group finds something suspicious in the exomes, it alerts the consented individuals so the affected individual can have clinical confirmation and, potentially, diagnosis of disease-related alterations in a CLIA-approved laboratory.

The researchers are also doing interviews with families who do receive such clinical results to learn more about whether they would have wanted to receive the genetic information when the individual was an infant, if possible.

Though her team is not enrolling parents of healthy newborns, Puck said it is understandably difficult to get informed consent from individuals who have just had a baby and do not have the immediate motivation of a childhood illness to consider.

Although she said it is a somewhat unexpected that uptake is not higher than it is for NICU infants in projects such as BabySeq, UNC's Powell is not all that surprised by the relatively modest enrollment numbers that are starting to trickle of out of some of the newborn sequencing projects.

"Families are given a balanced view of what this may or may not find and I think they are, appropriately, saying, 'Well, why do I really need that information? Will it be that helpful?'" she said. "We could find out something that could have implications for the child. But then again, we might get information that we don't know what to do with, or we won't know how to interpret the information," or it could lead to problems such as not getting long-term care insurance or disability insurance, she said.

Powell noted that researchers are in the process of putting together a paper on enrollment experiences in newborn sequencing studies, which may provide additional insights into what motivates parents to latch onto genome sequencing for their babies or steer clear of it.

Based on the preliminary patterns they've seen so far, her team is seeking IRB approval to make slight changes to their enrollment protocol, including an option for providing parental consent by Skype, since some families visiting the clinic have a parent in the military or working elsewhere who may not be able to come in in person. 

"It's a work in progress. We see where the problems are and see if our IRB will allow us to modify it," Powell said, though any major changes would have to be run past the US Food and Drug Administration, since the NC NEXUS study required a full Investigational Device Exemption application.

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