Janelle Hajjar (1,2), CJ Godfrey (3), Jeannine Fisher (3), Marc R. Gastonguay (1,2,3)
(1) University of Connecticut, Storrs, CT, USA, (2) Metrum Institute, Tariffville, CT, USA (3) Metrum Research Group, LLC, Tariffville, CT, USA
Objectives: To build a disease progression model of Duchenne muscular dystrophy (DMD), a rare disease, given public source 6-minute walk test (6MWT) data.
Methods: PubMed (www.pubmed.gov) was searched using PRISMA 2009 Standards [1] to obtain all publically available natural history or placebo data of the 6MWT in boys with DMD. Individual level 6MWT data of boys under 18 years of age were included in the analysis. Nonlinear mixed effects models were implemented with NONMEM® Version 7.3. A baseline model was fit with initial estimates based on summary statistics of literature population values. The final estimates of the baseline model were fixed in the fitting of a longitudinal disease progression model.
Results: Public data were available for 254 boys from 5 unique studies [2-6]. 4 boys were excluded due to inability to capture data. 129 boys had baseline data only. Baseline 6MWT across the population sample was described as an exponential function of age, with a sigmoid Emax maturational effect and exponential individual random effect. The final longitudinal model included baseline plus a linear slope with respect to elapsed time and an additive individual random effect. Observed baseline 6MWT (BL0) was a predictor of slope, dichotomized at BL0 <= 350 meters or > 350 meters. The standard deviation of the residual error was fixed to the literature value of 4 meters [5]. The point estimates and standard errors (SEs) of the slopes for <=350 vs >350 BL0 were -65.9 (20.2) meters/year and -24.8 (1.60e3) meters/year, respectively. The variances of the interindividual random effects for baseline and slope were 0.0596 (0.00377) and 9250 (1050), respectively. Inclusion of steroid use and study type (observational or trial setting) did not improve goodness of fit.
Conclusions: This analysis quantified the large variability in the longitudinal progression of DMD as measured by the 6MWT. Even after partitioning progression slopes for baseline 6MWT, considerable unexplained variability remained. The sigmoid component of the baseline model captured the maturational trend in boys ages 4-7 years old, when disease progression is often masked by childhood growth. The impact of additional covariates such as genetic information, medication history, or age of diagnosis is unknown, due to limitations in the public data sources. Future prospective analyses should consider evaluating these effects.
References:
[1] Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and MetaAnalyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097
[2] Brehm M-A, Kempen JCE, van der Kooi AJ, de Groot IJM, van den Bergen JC, etal. (2014) Age-Related Longitudinal Changes in Metabolic Energy Expenditure during Walking in Boys with Duchenne Muscular Dystrophy. PLoS ONE 9(12): e115200. doi:10.1371/journal.pone. 0115200
[3] Goemans N, van den Hauwe M, Wilson R, van Impe A, et al. (2013) Ambulatory capacity and disease progression as measured by the 6-minute-walk-distance in Duchenne muscular dystrophy subjects on daily corticosteroids. Neuromuscul Disord. 23(8) 618-623. doi: 10.1016/j.nmd.2013.05.006
[4] Mazzone E, Martinello D, Berardinelli A, Messina S, et al (2010) North Star Ambulatory Assessment, 6-minute walk test and timed items in ambulant boys with Duchenne muscular dystrophy. Neuromuscul Disord. 20(11) 712-716. doi: 10.1016/j.nmd.2010.06.014
[5] McDonald CM, Henricson EK, Han JJ, Abresch RT, et al. (2010) The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy. Muscle Nerve 41 500–510. doi: 10.1002/mus.21544
[6] Mcdonald CM, Henricson EK, Abresch RT, Florence JM, et al. (2013) The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: Longitudinal natural history observations over 48 weeks from a multicenter study. Muscle Nerve 48 343–356. doi: 10.1002/mus.23902
Reference: PAGE 25 (2016) Abstr 6008 [www.page-meeting.org/?abstract=6008]
Poster: Drug/Disease modeling - Other topics