In vulnerable young children, malformations of the chest wall and spine cause Thoracic Insufficiency Syndrome (TIS): the inability of the thorax to support normal respiration or lung growth. TIS is estimated to occur in 12.4 births per 10,000 and is associated with at least 28 pediatric diseases. Progressive TIS eventually reaches the point at which the thoracic engine of respiration is so damaged that Respiratory Insufficiency develops, often requiring supplemental oxygen or ventilator support. Outcome assessment of thoracic and spinal surgery for TIS is currently limited to static radiographs. CT scans are not practical because of radiation concerns. The usefulness of pulmonary function tests is limited since only children age 6 years or older can cooperate for spirometry and results summate multiple biomechanical deficits of TIS. A relatively new technique, dynamic Lung MRI (dMRI), has great potential to clearly define quantitatively, without radiation concerns, the dynamic biomechanical deficits and response to treatment of the dynamic thoraco-abdominal organs of young patients with TIS. The major hurdles currently preventing advance and innovation in TIS assessment and treatment include the lack of standardizable objective diagnostic measurement techniques that describe the 3D thoraco- abdominal structures, the dynamics of respiration, and the changes that take place with growth. The overarching goal of this R21 proposal is a paradigm-shifting effort to demonstrate innovative use of dMRI in its quantitative mode, which will be referred to as QdMRI in this proposal, for an objective evaluation and therapeutic outcome assessment of patients with TIS. The central hypothesis of this effort is that the proposed approach will enable the diagnosis and outcome assessment of treatment to be made quantitative and objective, and for the first time define the relationship between thoracic deformity/dysfunction and RI.
The specific aims of this project are: (1) To develop, test, and evaluate a QdMRI methodology and a biomechanical model for deriving key quantitative parameters from free-tidal-breathing dMRI image data for describing the 3D structure and dynamics of the thoraco-abdominal organs of TIS patients. The hypothesis related to this aim is that, with minimal user interaction, the QdMRI methodology will enable the precise estimation of key measures such as left & right chest wall and diaphragm excursion volumes and key thoraco- abdominal architectural parameters. (2) To objectively evaluate, via QdMRI, surgery for treating TIS. The underlying hypothesis is that the above parameters can act as standardized biomarkers for assessing outcomes of TIS surgery. To achieve Aim 1, a methodology will be developed to delineate major structures in the dMRI data sets and subsequently to derive the above parameters. To achieve Aim 2, the above key parameters will be estimated from the existing dMRI datasets of the pool of TIS patients in our database and the changes in the parameters from pre- to post-operative condition will be correlated with patient outcome.

Public Health Relevance

Congenital chest and spine malformations in childhood may cause devastating harm to pulmonary function because of thoracic insufficiency syndrome (TIS), and may result in ventilator dependency. We plan to study quantitatively pre- and post-operative dynamic MRIs of TIS patients and compare these quantitative measures to pulmonary function tests and patient outcome to understand the effectiveness of surgery. These methods have the potential to become a new metric for determining the effectiveness of pediatric spine and chest wall devices in restoring thoracic function for respiration.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Lin, Sara
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University of Pennsylvania
Schools of Medicine
United States
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Udupa, Jayaram K; Tong, Yubing; Capraro, Anthony et al. (2018) Understanding Respiratory Restrictions as a Function of the Scoliotic Spinal Curve in Thoracic Insufficiency Syndrome: A 4D Dynamic MR Imaging Study. J Pediatr Orthop :
Tong, Yubing; Udupa, Jayaram K; Odhner, Dewey et al. (2017) Interactive iterative relative fuzzy connectedness lung segmentation on thoracic 4D dynamic MR images. Proc SPIE Int Soc Opt Eng 10137:
Tong, Yubing; Udupa, Jayaram K; Ciesielski, Krzysztof C et al. (2017) Retrospective 4D MR image construction from free-breathing slice Acquisitions: A novel graph-based approach. Med Image Anal 35:345-359