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Hemophilia Genetic Testing Program Opens Data Repository for Research Applications in US


NEW YORK (GenomeWeb) – A pharma industry-funded program started a few years ago to provide free genotyping to hemophilia patients in the US has amassed blood samples and genetic data from more than 5,000 people, and has now opened that data up to researchers here in the US. 

In 2012, Bioverativ (then Biogen Hemophilia), the National Hemophilia Foundation, the American Thrombosis and Hemostasis Network (ATHN), and Bloodworks Northwest decided to offer free genetic testing to 11 hemophilia treatment centers in the US and store consenting patients' de-identified data in a repository for future research. The pilot effort was so successful that the collaborators decided to expand the program nationally a year later, and offer free genetic testing at 140 hemophilia centers. 

Their goal was to test patients in the hopes of identifying novel genetic mutations causing hemophilia, advance genetic research into the rare blood clotting disorder, and one day, may be even develop personalized treatment strategies. Having met their testing goal of 5,000 patients, in recognition of rare disease day on Feb. 28, the collaborators made the My Life, Our Future Research Repository available to US researchers. They are planning to open it up internationally next year.

For now, US researchers can apply for access to the samples and genetic data stored at Bloodworks Northwest and phenotypic data housed at ATHN, and investigate unanswered questions in hemophilia. "One of the questions that we hope can be answered through the repository is to understand why patients with the same clotting factor activity level sometimes have different bleeding phenotypes," said Barbara Konkle, associate chief scientific officer at Bloodworks Northwest, where patients samples are genetically tested, and chief investigator of the repository. "That may be due to genes other than Factor 8 or Factor 9 or something about their Factor 8 or 9 variants."

Hemophilia occurs in patients with mutations in either the F8 or F9 genes, which leads to a deficiency of the blood-clotting proteins Factor VIII and Factor IX, respectively. Changes in the F8 gene are responsible for hemophilia A, while mutations in the F9 gene cause hemophilia B. Hemophilia-causing gene mutations are mostly inherited, though 30 percent of patients have no family history of the condition.

The genetics of hemophilia is complex, with some 4,000 genetic variants known to cause the disorder. In building the repository, "we've learned that there is a lot of genetic variation in Factor 8 and Factor 9," Konkle said. "We keep finding new variants, even though this has been studied broadly." The genotyping initiative has so far identified 600 new hemophilia-causing variants.

The University of Washington first analyzes the samples using next-generation sequencing to genotype F8 and F9 genes. Then, the identified variants are confirmed by Bloodworks Northwest via direct sequencing or enzyme restriction digest methods on a separate aliquot.

During the course of the testing program, Konkle said her team learned how to use a modified NGS approach to genotype patients with severe Factor VIII deficiencies. "About half of severe Factor VIII deficiency is due to structural variation and next-generation sequencing is challenging," she said.

In order to detect F8 intron 1 and intron 22 inversions, Bloodworks Northwest worked with Jay Shendure's lab at the University of Washington to apply a method similar to that described by Liliana Rossetti and colleagues using inverse-shifting PCR. This method allowed capture of "ligated mutant and reference sequences in one reaction," Konkle explained in an email. 

In the years that the My Life, Our Future Research Repository has been testing patients and building its repository, genetic data collaborations have taken off. A recent survey by PricewaterhouseCoopers noted that such data collaborations are on the rise. Moreover, data sharing among stakeholders and in open-access repositories is a priority within big government-funded projects, such as the Precision Medicine Initiative and the Cancer Moonshot. 

According to Konkle, the hemophilia repository has joined the NHLBI's Trans-Omics for Precision Medicine Program, which is collecting whole-genome sequence and other omics data for the NIH's larger precision medicine efforts, including the All of Us Research program. Through this program NHLBI funds whole-genome sequencing for cohorts that have other omics data, and almost 5,000 of the hemophilia samples in the My Life, Our Future Research Repository will sequenced. That WGS data and limited phenotypic information will be available broadly through dbGap, though more extensive, deidentified phenotypic information can be obtained through the My Life, Our Future platform.

Whenever genetic data and linked phenotypic data are available in a repository, there are concerns about reidentification. "From the beginning we knew it was important for scientific discovery to have consent for whole-genome sequencing," Konkle said. "But then, we needed the patients and the parents of children to understand the implications of that."

Within the hemophilia testing program, patients are consented at treatment centers where their data and samples are coded and scrubbed of personal identifiers. The repository also has a system of coding data and samples. Although the genetic testing lab has permission to go back to patients for additional samples, because the lab doesn't have any personal identifiers, the request must be made through the treatment centers.

Although genetic testing is free for hemophilia patients through this program, donating their samples and data to research is entirely voluntary. But most patients agree to contribute. As of Feb. 24, 7,500 patients had enrolled in the project since 2012, and when patients and parents of children are asked to contribute their data and samples, 83 percent agree.

When Bioverativ decided to fund genetic testing through this program, they said they would do so for three years and aim to test between 5,000 and 10,000 hemophilia patients. In doing so, the firm not only committed to advancing genetic research, but to improve access to testing conducted for family planning purposes. This testing is not widely covered by payors and costs can range from $500 to $3,000, depending on the technique and the lab performing the service.

The testing program will continue to enroll patients through 2017. Konkle and her colleagues will still test males but are focusing on enrolling females who are mutation carriers or potential carriers of hemophilia.

The blood clotting disorder is exceedingly rare in women. Around 1 in 5,000 males are born with hemophilia A, and 1 in 25,000 men are born with hemophilia B. Females can be mutation carriers but seldom get the disease. "We plan to have 2,000 females in the research repository by the end of this year," Konkle said.

Researchers interested in gaining access to the clinical samples and genetic and phenotypic data must submit a proposal that will be evaluated by a committee with expertise in genetics and hemophilia. ATHN will coordinate with Bloodworks Northwest to deliver the deidentified data and samples to investigators with approved research proposals.