Therapeutic intervention in patients with DMD during early childhood is likely to yield the most effective preservation of muscle. Detection of treatment effects on muscle function at this stage of disease, however, is challenging. Younger patients with DMD who are still growing are likely to show improvements over time in functional performance measures, such as 6MWD, until approximately 7 years of age regardless of treatment for DMD ,,
. Meanwhile, older patients with DMD who are beyond the plateau phase may show overt decreases over time in functional performance measures, such as 6MWD. Converting 6MWD to %-predicted 6MWD may help to distinguish normal growth and development from treatment effects. Within the context of clinical trials, these age- and growth-related factors have the effect of increasing the variability of changes from baseline, thereby requiring larger sample sizes 
Furthermore, functional performance results have been used in the past to determine minimum threshold values that can predict future loss of function. For example, a 10-meter run/walk time of ≥12 seconds has been correlated with an ~90% risk of losing ambulation during the following year 
. This 12-second threshold, which theoretically translates to a 6MWD of 300 meters assuming the same pace can be maintained (ie, 12 seconds divided by 10 meters equals a velocity of 0.83 meters per second, which multiplied by 6 minutes equals 300 meters), has been used to justify exclusion criteria for clinical trials to help maximize the likelihood that participants will remain ambulatory during the course of a 1-year study. Because it is likely the same pace cannot be maintained by a patient with DMD for 6 minutes, the 12-second threshold realistically translates to a 6MWD <300 meters. Nonetheless, such thresholds based on absolute values ignore the fact that younger and older participants are on opposite sides of the “inverted U” distribution and therefore a 6MWD that reflects nearly normative function in the younger child may indicate a notable degree of impairment in an older child. Future studies should address whether minimum threshold values based on %-predicted values may be more appropriate for predicting loss of function in DMD.
Normal growth and development should be taken into account when interpreting absolute values of functional measures in patients with DMD, as the trajectory of changes in functional performance measures over 1 year may vary depending on age and related characteristics such as height. The most straightforward way to account for normal growth and development is to evaluate the performance of a DMD boy relative to the typical performance of age- and height-matched healthy peers by calculating a %-predicted value. While this is a common approach in pediatric specialties such as pulmonology ,,
, it has not yet been commonly employed in the functional assessment of individuals with neuromuscular diseases.
When the ATS guidelines for conducting the 6MWT were published in 2002, it was not yet known whether change in 6MWD should optimally be expressed as an absolute value, a percentage change, or a change in the %-predicted value. Citing a need for further research, the ATS guidelines recommended expressing change in 6MWD be expressed as an absolute value 
. However, in the past few years, pediatric normative data have become available that may be used to calculate %- predicted 6MWD. Among several regression models identified in the literature, the results presented here show that the Geiger equation is most suitable for use in calculating %-predicted 6MWD in boys with DMD. Notably, the 6MWT method employed by Geiger encouraged subjects to walk as far as possible by providing consistent feedback 
, a departure from the ATS guidelines and unlike the other normative studies but similar to the method for conducting the 6MWT in boys with DMD 
. Perhaps due to this methodologic similarity, the Geiger equation very accurately predicted the 6MWD results in our healthy control cohort.
Although similar, the Geiger 6MWT method and ours are not identical. For example, Geiger et al used a 20-m track, while our track was 25 m. Geiger et al used encouragement in 1-minute intervals and a measuring wheel that displays the instantaneous walking distance, while our method employed a “safety chaser” who walked behind the participant and provided encouragement at 15-second intervals. Despite these methodologic differences, based on our experience we recommend using the Geiger equation to determine %-predicted 6MWD in the DMD population, at least until a regression model based upon our 6MWT method has been developed; this work is ongoing.
Our previous reports of 6MWD data in boys with DMD at baseline and longitudinally over 12 months ,
, and 6MWD data subsequently reported by Mazzone et al 
, both indicated a moderate degree of increase in 6MWD over a 1-year period in younger children (ie, <7 years old) with DMD. These data and normative data in typically developing children show that this increase is consistent with normal growth and development 
. In the present study, we show that children with DMD as young as 4 years of age show on average a 20% deficit in 6MWD relative to healthy peers, and that this deficit remains somewhat stable until middle to late childhood. Beginning between ages 7 and 8, however, the relative reduction in ambulatory function accelerates at an increasing pace to a point where adolescents between ages 10 and 12 may lose function relative to controls at 20% per year or more. Understanding the functional changes observed in DMD patients during their development is critical in clinical trial development, as the effect of therapeutic intervention in a given patient population can be more variable than anticipated (or more difficult to detect) depending on the maturational status of the DMD patient.
In comparison with our previous presentations of data from this cohort, we show that early gains in function that affect overall groupwise change estimates can be “flattened”, or normalized using %-predicted values. While we obtained our data from a small and somewhat heterogeneous cohort, these results further demonstrate that increases in 6MWD are proportional to normal growth up to about age 7 in boys with DMD, which is consistent with the commonly held concept of the “honeymoon period” in DMD during which functional gains that result from growth and development keep pace with disease progression such that %-predicted 6MWD is stable at ~80% of healthy controls. Past age 7, boys with DMD experience substantial declines in %-predicted 6MWD. Additional longitudinal studies of %-predicted 6MWD using larger cohorts of boys with DMD across a wider age range are planned.