SAN FRANCISCO (GenomeWeb) – The HudsonAlpha Institute for Biotechnology plans to sequence the genomes of newborns in neonatal nurseries with birth defects or other signs of a genetic disorder under a four-year $10 million grant from the National Institutes of Health.
The project is part of a second wave of funding awarded last year under the NIH's Clinical Sequencing Exploratory Research program. The new projects — all part of the Clinical Sequence Evidence-Generating Research (CSER2) consortium — will focus on implementing genome sequencing into clinical care, specifically for medically underserved populations, and will evaluate its impact on health outcomes.
HudsonAlpha has partnered with the University of Alabama at Birmingham, Children's Hospital of Alabama, and the University of Mississippi in Jackson. The goal is to enroll 1,500 newborns, particularly from underserved populations in the south, including African American families and families who live in rural areas.
Greg Cooper, a faculty investigator at HudsonAlpha, said the focus on historically underserved populations is particularly important because "we believe that genomics technologies will have clinical benefits, and so we want to make sure that those benefits are broadly distributed in a socially equitable way."
Genomic research has focused primarily on populations of European descent, but in recent years, researchers have increasingly recognized the importance of including other groups. Diversity in genomics studies is important both to ensure that everyone benefits from advances in genomic medicine and to improve the quality of research. There's been an increasing awareness that variant allele frequencies differ between populations, so what may be a rare variant in one population may be a common variant in another. Understanding these differences will help researchers better interpret which variants are disease causing and which are benign, and may also help spur new discoveries.
The NIH has begun placing emphasis on increasing diversity in genomic studies, which will be a major focus of all the CSER2 projects, with each site focusing on populations that are unique to its geographical location.
For instance, Cooper said that there is a large rural population in Alabama, so one important aspect will be to address the unique challenges that population faces, such as travel to clinics. Similarly, the group hopes to address challenges that are specific to the African American community and to figure out "what are the barriers and obstacles to genetic testing and how can we solve them," Cooper said. "There will be a major effort on community engagement."
The primary goal, however, will be to see whether sequencing the genomes of sick infants leads to better outcomes than traditional testing. HudsonAlpha will be performing the sequencing and will return diagnostic results, Cooper said. In addition, the researchers will continue to follow up with the families to study how the diagnosis impacts the child's health long term. "We'll follow up with the pediatrician and the family to see to what extent that genetic information led to changes in treatment or decision making," Cooper said. Any molecular diagnosis that is made will be entered into the patient's medical record, and families will also have the option of getting secondary findings related to the 59 genes deemed important by the American College of Medical Genetics and Genomics. Cooper said that one change from the first CSER project to the second is that in the first, where HudsonAlpha sequenced children with unknown genetic disorders, families could pick and choose the various types of secondary findings they wanted to receive. For instance, they could choose to get information on genes related to hereditary cardiovascular disorders but not hereditary cancers. Cooper said that for the second project, the team simplified that option to either a yes or a no to all 59 genes.
Although the researchers will return diagnostic information to families, Cooper said, the primary goal is not to make immediate care decisions for babies, in contrast to a program at Rady Children's Institute for Genomic Medicine that is sequencing the genomes of critically ill infants in the neonatal intensive care unit. At Rady, the group led by Stephen Kingsmore has been continually working on driving down sequencing and analysis time to under 24 hours. Clinicians are often using the sequencing results to make immediate treatment and clinical management decisions for those babies.
"Our primary goal is diagnosis of congenital conditions that we think will be with these children chronically," Cooper said. "We're not doing rapid turnaround where we're designing this to be used for acute clinical care. The process, [as well as] logistical and pragmatic challenges of that are too large" for the scope of the study, he said.
HudsonAlpha expects to return results in around two months from the time that a child is enrolled. However, he said, the center is interested in also doing a pilot study of a smaller subset of the patients where they use a rapid-turnaround protocol. Currently, he said, Shawn Levy, director of HudsonAlpha's Genomic Services Lab, has a protocol whereby results could be returned in about five to seven days, however that's cost prohibitive to do for all 1,500 patients and comes with additional logistical challenges. "To do that, when a sample shows up at the lab, you have to have a technician ready to do the extraction, a flow cell ready to run, and then a CPU ready to do the computing," he said.
The other issue with turnaround time is Sanger validation. Currently, HudsonAlpha Sanger-validates variants before returning a diagnosis, "which we think is very important, especially for very rare variants, and especially if a clinician is going to be making medical decisions" based on the diagnosis, he said. However, even a rapid Sanger process takes a day or two,.
Thus far, Cooper said, around 15 genomes have been sequenced, but he expects the enrollment rate to pick up this year.
As part of the first CSER grant, HudsonAlpha researchers performed whole-genome sequencing on around 600 children and their parents with unexplained genetic disorders, finding diagnoses for around 30 percent. In that study, patients ranged in age from 2 years to 18 years and parents tended to report greater utility and benefit of the sequencing when it was done at an earlier age. "Many of those families had been having problems since infancy, so if they were given a diagnosis even earlier, they would have potentially benefitted even more," Cooper said. This concept was in part what motivated the CSER2 project to focus on infants. "Many pediatric genetic conditions show up early in life," he said, so the goal is to see whether implementing sequencing as a first-line test when those problems begin to manifest, as opposed to as a last resort after years of testing by other means, leads to better results.
In addition, researchers are following up on some of the cases from the first CSER project who did not receive a diagnosis, applying Pacific Biosciences technology to see whether longer sequencing reads can help find potential structural variants that are difficult to detect with shorter reads.
For CSER2, there are no current plans to incorporate PacBio sequencing, but Cooper said that if the method proves successful at solving some of the original CSER cases, the team could look for external funding to apply it to this next project.
Cooper predicted that genome sequencing will eventually become standard of care for diagnosing genetic disorders and said that the CSER projects would be useful in understanding the utility of sequencing on health outcomes. Currently, he said, sequencing is too often used as a "tool of last resort," but in the future, he hopes that the "threshold for ordering a genome will be minimal, especially given that the costs are coming down and will soon be on par with an MRI or even less."
However, in order for genome sequencing to become a first-line test, researchers will have to demonstrate not only clinical utility but also cost effectiveness. Cooper said that although economic analyses are not part of the original CSER2 grant, the team is in discussions with collaborators at UAB who specialize in healthcare billing to see whether they might be able to apply for other grants to fund that type of analysis.
Initial results from other groups have found that sequencing as a first-line diagnostic may be cost effective. For instance, a study published last month by Kingsmore's group at Rady Children's found that of 42 babies who were sequenced, 43 percent received a diagnosis, resulting in net healthcare savings of $128,544, and critically, that sequencing avoided morbidity in 11 babies, and major morbidity in four.
Earlier this week, a group from the Murdoch Children's Research Institute in Melbourne, Australia reported that out of a cohort of 80 infants with suspected monogenic disease who had exome sequencing, changes in clinical management based on the results led to average savings of A$1,578 ($1,186) per quality-adjusted life year gained.