What does it take to perform a four-year, multiple-site clinical research study screening 37,649 newborn babies for a possible genetic disease? Lots of people, lots of time and lots of data. Were the Center for Gene Therapy and Clinical Research Services teams busy during their Duchenne muscular dystrophy newborn screening project? Absolutely. Here is a brief look at why.
Developing a good team
One word: manpower. To transform a research idea into action, the Center for Gene Therapy and Clinical Research Services staff (Chris Shilling, Chelsea Rankin, Lauren Bird, Brent Yetter, Kandice Roush, Dr. Jerry Mendell, Paulla Davies, Grace Wentzel, et al) worked together on the many and diverse aspects of this multi-site, investigator-initiated study, from design and coordination to implementation and evaluation.
The team worked closely with the Ohio Department of Health to understand current newborn screening guidelines. The Ohio Department of Health laboratory also performed CK testing on all of the dried blood spots obtained throughout the study. Test results were reported to the primary care physician or directly to the family and the Nationwide Children’s team helped schedule appointments with the nearest MDA clinic for further testing if CK elevations were detected.
Members of the DNA sequencing laboratory at the University of Utah performed DNA testing on the initial dried blood spot if the sample had elevated CK.
Gathering lots of good pilot data
Before the team could start any newborn screening, they had to determine guidelines for creatine kinase (CK) analysis (what CK level in the blood would be considered abnormal during the study, how soon after birth did samples need to be collected, etc.). So they analyzed 30,547 anonymous dried blood spot samples.
After testing guidelines were determined, the pilot study began, screening 6,928 newborns at major birthing hospitals in Columbus and Cincinnati, Ohio. During this pilot, 100 subjects had CK levels exceeding the testing threshold and required DNA analysis. The pilot study provided the impetus to study the CK threshold statewide.
Expanding the study to the entire state
During the state-wide screening phase, 43 Ohio hospitals actively recruited mothers and babies to participate in the study, all of which were managed centrally through Nationwide Children’s. Our Clinical Research Services team oversaw each site’s staff to ensure compliance with research Good Clinical Practices. Clinical Research Services received data from every blood spot analysis and monitored the data for quality and accuracy. The team was also responsible for keeping track of each participating hospital’s IRB application, site training and education, consenting, logistics of all of the blood spots and coordinating any needed family follow up based on test results. An additional 10,937 newborns were screened for this statewide study.
Getting even more data
In order to increase sample size and validate the two-tier screening process, a fourth phase of the study involved screening a large cohort of de-identified newborn samples anonymously. This increased the sample size by 19,884 newborns.
Over the course of the study, 37,649 newborn boys were screened and six were discovered to have DMD gene mutations.
Analyzing the data and sharing the results
The paper documenting Nationwide Children’s DMD newborn screening process recently appeared in the Annals of Neurology. Evidence shows that the approach could be implemented if approved by state or national regulatory bodies.
Nationwide Children’s work is already being recognized in the United Kingdom and Europe as they work through their plan for DMD newborn screening. Dr. Mendell has been invited to a newborn screening conference in the Netherlands with prominent European investigators studying muscular dystrophy.
Realizing what the efforts could mean for future generations. Then preparing to do more
If implemented, the newborn screening process developed and validated by Nationwide Children’s would provide the first official DMD newborn screening in the United States and serve as a model to replace the previous three-step screenings that have since been discontinued worldwide. It could mean that every year, 20,000 boys who would normally lose the ability to walk by their teenage years could have access to treatments earlier and potentially lead longer, more physically fulfilling lives. And families could have time to prepare.
Yet, there is more work to be done. Treatments still need to be improved and a cure to be found. If successful therapies for dystrophinopathies are one day available for newborns, a pathway for referral would need to be built into the screening program.
Still, this research effort is a testament to what Nationwide Children’s faculty and staff is capable of. And it’s something we can all be proud of.
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