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Pilot NBS project to prospectively identify
and follow infants with SMA
Kathryn Swoboda, Marci Sontag,
Jeff Botkin, Steve Dobrowolski,
NBSTRN: Amy Hoffman and the
Bioethics Work Group, Amy Brower
and the Clinical Centers Workgroup
SPINAL MUSCULAR ATROPHY (SMA)
• Most common recessive cause of infant lethality
• Incidence 1 in 6,000-10,000 births
• Motor neuron degeneration results in progressive
muscular atrophy, weakness, bulbar insufficiency and
premature death in majority of those affected
• Natural history study data suggest that early
intervention necessary to improve outcomes for the
severe infantile phenotype (50% of cases)
SMA Genetics
• SMN1 and SMN2 reside in an inverted
duplicated region on chromosome 5q13
• Critical bp change in exon 7 alters splicing, resulting
in truncated protein deleted for that exon
• But 10% fl product from SMN2 identical to that from
SMN1
• 95% of SMA subjects have a homozygous
deletion of exon 7 in SMN1
SMN2 dosage predicts phenotype
From Utah SMA Natural History Database
N=301
SMA type I accounts for 50% of cases
•Infantile onset
•Respiratory and bulbar
insufficiency
•Generalized weakness,
hypotonia
•Premature death in majority
by age 2 yrs
SMA type II accounts for 20-30%
•Significant respiratory morbidity,
scoliosis, hip dislocation, joint
and muscle contractures, early
mortality
Conceptual Framework: NBS in SMA • Pilot data from STOP SMA study suggests
early vs later intervention may substantially
improve outcomes
• Evidence-based process may not be adequate
to prove efficacy first due to early and severe
disease progression
• Early screening provides opportunity to assess
hypothesis that early identification will
improve outcomes with emerging new
therapies
“Real time” DNA-based NBS pilot for SMA in Utah and Colorado
• Births: 55,000/yr in Utah, 70,000/yr Colorado
– Subset of infants will be screened, due to challenges with
acceptance of DOH programs with an opt-out process, in
spite of broad public support in both states
• Goal: confirmation of diagnosis within three days of
obtaining newborn spot, first face to face contact
within 3 weeks of birth
• Prospective followup of infants with data entered
onto CRFs on forms designed in collaboration with
NBSTRN LTFU workgroup
Background – SMA Pilot in Colorado
• Initial pilot study was planned to be implemented through Department of Health using newborn screening dried blood spots – Approval was obtained through Colorado Multiple
Institutional Review Board (COMIRB) at University of Colorado
• After 2 years of discussion it was decided that there were challenges that would not allow the study to proceed through the Department of Health
Background – SMA Pilot in UT
• Initial plan to implement pilot though the Utah Department of Health using dried blood spots using an opt-out consent model
– Initial IRB approval by University of Utah
• However, in spite of broad population support, DOH IRB rejected this proposal
• Ultimately, after extensive discussion, IRB approved by DOH using opt-in consent model
Revised Plan- Colorado
• Infants will be screened with a separate dried blood spot, following state mandated NBS
• Sample will be sent to ARUP through research coordinators at the Colorado School of Public Health (CSPH)
– Coordinators will initially pick up samples personally. Later samples will be shipped to CSPH for logging and tracking before shipping to ARUP
Revised Plan- Utah • Infants will be screened using residual sample
from state-mandated NBS, but only following a witnessed opt-in consent documented directly on the card prior to collection
• Sample will be sent to the UTAH DOH laboratory, then deidentified prior to sending to ARUP for screening using the wave-melt technology
• Sample will be reidentified only if positive; investigators and DOH followup program will collaborate closely to contact families
Study Oversight and Consent
• Institutional Review Board Approval required through each major hospital system, therefore only larger systems are to be included
• Mothers provided brochure in hospital explaining study and opt-out procedures (CO)
• Mothers provided brochure in hospital and opt-in procedure (UT)
• Mother has 2 weeks from the time of baby’s birth to opt-out of participation
Opt-Out of Participation: CO
• Opt-out most closely matches the model used in Colorado for Newborn Screening
– Deemed to be minimal risk by COMIRB
– Full consent not feasible
• To opt-out, mother can:
– Call a toll free number
– Visit a secure website (REDCap database structure)
– Tell nurse at hospital (card will be marked as opt out for tracking purposes only)
Current status: CO
• IRB approval in place for hospitals covered by COMIRB (2 birthing hospitals, regional children’s hospital)
• IRB approval pending at largest birthing system – expected by June 2013
• Additional hospital systems are identified
• Training has occurred in first hospital and initial screening will begin in April 2013 – used as a pilot to streamline procedures
• Anticipate ~42,000 births/year to be eligible for screening (out of ~70,000 in state)
Current Status: UT
• IRB approval in place for the University of Utah
• Awaiting approval for other major hospital systems, expected to occur sequentially over next several months
• Anticipate maximum uptake ~ 35K births (as opposed to 55K had we been able to use an opt-out model
Critical Contributions from NBSTRN
• Provision of bloodspots via Michigan biobank (Steve Dobrowolski PI) to confirm performance of wave melt screening technology
• Referral and support for other newborn screening programs interested in collaboration (discussions ongoing with Wisconsin program)
• Support for design of CRFs for LTFU (now completed)
Acknowledgements • Funding source: NICHD
• Rodney Howell and Tiina Urv
• Steve Dobrowolski
• NBSTRN especially Amy Brower, Amy Hoffman, Mike Watson
• CHOP especially Jennifer Loutrel and Stacey Wrazien
• Colorado team, led by Marci Sontag
• University of Utah team, led by Kathryn Swoboda, Jeff Botkin
– THANK YOU FOR YOUR ATTENTION