STUDY DESIGN AND METHODS FOR EVALUATING SUSTAINED UNRESPONSIVENESS TO PEANUT SUBLINGUAL IMMUNOTHERAPY Public Deposited

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  • March 21, 2019
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  • Chaudhari, Monica
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
Abstract
  • The length of time off-therapy that would represent clinically meaningful sustained unresponsiveness (SU) to peanut allergen remains undefined. Our work has three-fold objectives: first, to delineate aspects of the altered clinical trial design that would allow us to assess effectiveness of sublingual immunotherapy (SLIT) in achieving SU; second, to discuss methodology for evaluating the time to loss of SU and associated risk factors in context of the proposed study design; finally, to develop a flexible methodology for assessing mean reverting threshold and prognosis of SU failure in the presence of study risk factors. Failure refers to the loss of SU upon therapy cessation in peanut allergic children who are administered sublingual immunotherapy (SLIT). The salient feature of the new design is the allocation scheme of study subjects to staggered sampling timepoints following therapy suspension when a subsequent food challenge is administered. Due to a fixed sequence of increasing allergen doses administered in a challenge-test, the subject’s true threshold at either occasion is interval-censored. Additionally, due to the timing of subsequent DBPCFC, the time to loss of SU for subjects who pass the DBPCFC at study entry is either left- or right-censored. In this thesis, we elaborate on the features of the study design, develop and extensively validate methods to evaluate study end points and discuss their potential to inform individualized treatments. The thesis is compartmentalized as follows: (i) an innovative clinical trial design that aims at studying SU to SLIT; (ii) a newly developed mixture proportional hazards model for evaluating the time to loss of SU in context of the study generated interval-censored data subject to instantaneous failures; (iii) a time-dependent Ornstein Uhlenbeck (OU) diffusion process for modeling immunologic SU degradation trajectories using stochastic differential mixed effect model (SDMEM) framework; (iv) the estimation of mean-reverting threshold and prognosis of the loss of SU; (v) lastly, the clinical implementation and future scope of work. Through this work, we are presented with an opportunity to dedicate these inter-connected parts to three core issues of failure: model description, prediction and prevention.
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  • In Copyright
Advisor
  • Koch, Gary
  • Kosorok, Michael
  • Zeng, Donglin
  • Hudgens, Michael
  • Kim, Edwin
Degree
  • Doctor of Public Health
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017
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