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. 2016 Aug;5(8):437-45.
doi: 10.1002/psp4.12097. Epub 2016 Aug 2.

Modeling Variability in the Progression of Huntington's Disease A Novel Modeling Approach Applied to Structural Imaging Markers From TRACK-HD

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Free PMC article

Modeling Variability in the Progression of Huntington's Disease A Novel Modeling Approach Applied to Structural Imaging Markers From TRACK-HD

J H Warner et al. CPT Pharmacometrics Syst Pharmacol. .
Free PMC article

Abstract

We present a novel, general class of disease progression models for Huntington's disease (HD), a neurodegenerative disease caused by a cytosine-adenine-guanine (CAG) triplet repeat expansion on the huntingtin gene. Models are fit to a selection of structural imaging markers from the TRACK 36-month database. The models are of mixed effects type and should be useful in predicting any continuous marker of HD state as a function of age and CAG length (the genetic factor that drives HD pathology). The effects of age and CAG length are modeled using flexible regression splines. Variability not accounted for by age, CAG length, or covariates is modeled using terms that represent measurement error, population variability (random slopes/intercepts), and variability due to the dynamics of the disease process (random walk terms). A Kalman filter is used to estimate variances of the random walk terms.

Figures

Figure 1
Figure 1
Plots of Akaike information criterion (AIC) for the Base model fitted with fixed values of L between 21 and 40 for all imaging biomarkers.
Figure 2
Figure 2
Global descriptive plot for Y=logit(100×Striatum(Iowa)ICV): Full Model. Panel (a): Y1=YdC vs. AGE in Healthy Controls; Panel (b): Y2=YSC(AGE)dHD vs. cytosine‐adenine age product (CAP30) in Huntington's disease (HD) participants; Panel (c): Y2=YSC(AGE)dHD vs. CAP(Lopt) in HD participants. Based on Eqs. 2 and 3.
Figure 3
Figure 3
Simulated trajectories for striatum (Iowa): Huntington's disease (HD) participants trajectories are simulated under the Base, Random Slope (RS), Random Walk (RW), and Full models in the population of HD participants. The simulations are based on 50 replicates and assume cytosine‐adenine‐guanine (CAG) lengths of 42. Trajectories are simulated and plotted for ages starting at 18 years and ending at 70 years. Simulated trajectories are for a male equally likely to be selected from any of the four sites.
Figure 4
Figure 4
Scatter visual predictive checks for striatum (Iowa): full model simulations use 1,000 replicates for healthy controls and gene‐positive Huntington's disease (HD) subjects with cytosine‐adenine‐guanine (CAG) lengths of 39, 40, 41, 42, 45, 48, 50, and 59. Simulated observations are for men from site 4. All observed data points are adjusted for site and gender. Solid black lines represent 5%, 50%, and 95% quantiles of the distribution of predicted observations. Solid green lines indicate model population predictions.

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References

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