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Evaluation of Neimann-pick type C1 disease using mixed effects models

Backman, Michael (2016) Evaluation of Neimann-pick type C1 disease using mixed effects models. Master's Thesis, University of Pittsburgh. (Unpublished)

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Niemann-Pick Type C1 (NPC1) is an autosomal neurologic pediatric orphan disease, with death occurring by age 20-25. It is estimated that 1 in 150,000 people in the United States (US) and 1 in 100,000 people in the European Union (EU) suffers from NPC1. The disease results from NPC1 gene mutations which cause defective protein activity, leading to harmful levels of cholesterol and sphingolipids in cells.
Using data from a natural history study and a phase 1 study we investigated the efficacy of a potential treatment for NPC1 in patients aged 6 to 26 with multiple follow-up visits. To evaluate the change in severity of neurologic manifestations, we focused on nine different measures: dietary restrictions, diminished lip strength, diminished tongue strength, dysarthria, ability to consume liquids, risk of laryngeal penetration when consuming liquids or solids, ability to consume solids, speech difficulties, and swallowing difficulties. The primary objective of our analysis evaluated the efficacy of the proposed treatment in reducing the aforementioned symptoms of NPC1. For each symptom, a random intercept mixed-effects model was fit incorporating the factors of time, treatment, and their interaction as potential predictors.
Our strategy has certain advantages over a traditional randomized clinical trial (RCT) as it uses patients enrolled from an ongoing natural history study for which we already have some data on the progression of the disease. Furthermore, it provides a pool of patients from which to recruit phase 1 participants. From an analytic point of view, it provides an efficient use of the available data and an alternative design to an RCT that requires greater sample sizes which would be difficult to obtain in the setting of a rare disease. The utilization of our study design can expedite orphan disease research by decreasing the amount of patients necessary to reach meaningful conclusions from efficacy studies. For these reasons, our approach provides a practical alternative in evaluating efficacy of treatment in rare/orphan disease research, a very current public health issue.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Backman, Michaelmichaelchaimbackman@gmail.comMCB540000-0002-4818-5978
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorArena, Vincent C.arena@pitt.eduARENA
Committee MemberPike, Francisfrp3@pitt.eduFRP3
Committee MemberTalbott, Evelyn O.eot1@pitt.eduEOT1
Committee MemberWeissfeld, Lisa
Date: 27 January 2016
Date Type: Publication
Defense Date: 19 November 2015
Approval Date: 27 January 2016
Submission Date: 3 December 2015
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 63
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Biostatistics
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: NEIMANN-PICK TYPE C1 DISEASE
Date Deposited: 27 Jan 2016 21:00
Last Modified: 15 Nov 2016 14:31


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