Categorising trajectories and individual item changes of the North Star Ambulatory Assessment in patients with Duchenne muscular dystrophy

Abstract

Functional variability among boys with Duchenne muscular dystrophy (DMD) is well recognised and complicates interpretation of clinical studies. We hypothesised that boys with DMD could be clustered into groups sharing similar trajectories of ambulatory function over time, as measured by the North Star Ambulatory Assessment (NSAA) total score. We also explored associations with other variables such as age, functional abilities, and genotype. Using the NorthStar Clinical Network database, 395 patients with >1 NSAA assessment were identified. We utilised latent class trajectory analysis of longitudinal NSAA scores, which produced evidence for at least four clusters of boys sharing similar trajectories versus age in decreasing order of clinical severity: 25% of the boys were in cluster 1 (NSAA falling to ≤ 5 at age ~10y), 35% were in cluster 2 (NSAA ≤ 5 ~12y), 21% in were cluster 3 (NSAA≤ 5 ~14y), and 19% in cluster 4 (NSAA > 5 up to 15y). Mean ages at diagnosis of DMD were similar across clusters (4.2, 3.9, 4.3, and 4.8y, respectively). However, at the first NSAA assessment, a significant (p<0.05) association was observed between earlier declining clusters and younger age, worse NSAA, slower rise from supine, slower 10 metre walk/run times, and younger age of steroid initiation. In order to assess the probability of observing complete loss of function for individual NSAA items, we examined the proportion of patients who shifted from a score of 1 or 2 at baseline to a score of 0. We also assessed the probability of gain of function using the inverse assessment and stratified the probability of deterioration, improvement-or static behavior-by age ranges and using baseline functional status. Using this tool, our study provides a comprehensive assessment of the NSAA in a large population of patients with DMD and, for the first time, describes discrete clusters of disease progression; this will be invaluable for future DMD clinical trial design and interpretation of findings.

Fig 1

NSAA total score trajectories for individual patients by age (in grey) and the fitted mean and 95% confidence interval (in black). Each grey line represents NSAA total scores from an individual patient plotted versus age; the population mean and its 95% confidence bands are shown in black. NSAA, North Star Ambulatory Assessment.

Fig 2

Histograms of changes in NSAA total scores over (A) 1 year, (B) 2 years, and (C) 3 years among boys with DMD belonging to different age ranges. DMD, Duchenne muscular dystrophy; NSAA, North Star Ambulatory Assessment.

Fig 3

Individual patient (A) and fitted mean (B) trajectories of NSAA total score by latent class; individual patient trajectories of (C) 10 metre walk/run velocity and (D) velocity of timed rise from supine, all stratified by latent class. m/s, metres per second; NSAA, North Star Ambulatory Assessment; s, seconds.

Fig 4. Percentages of patients demonstrating function (NSAA item score > 0) by age and by trajectory class for four of the NSAA items.

(A) rise from floor, (B) run, (C) jump, and (D) hop on one leg. NSAA, North Star Ambulatory Assessment.

Fig 5. Shifts in NSAA item scores over 1 year: stratification by age.

Annualised probabilities of (A) deterioration (shift down); (B) stable function (no change); or (C) improvement (shift up) in the population with DMD stratified by age groups. DMD, Duchenne muscular dystrophy; L, left; NSAA, North Star Ambulatory Assessment; R, right.

Fig 6. Shifts in NSAA item scores over 1 year: stratification by functional status.

Annualised probabilities of shift up in NSAA item scores when stratified by (A) 10 metre walk/run and (B) rise from supine; probability of shift down in (C) 10 metre walk/run and (D) rise from supine. 10MWR, 10 metre walk/run; s, seconds; DMD, Duchenne muscular dystrophy; L, left; NSAA, North Star Ambulatory Assessment; R, right.