Rating scales, based on modern psychometric validation, are increasingly used as primary outcome measures in natural history studies and clinical trials. The quality of the rating scale has the potential to influence the outcome of clinical trials and patient care.17
We performed a rigorous development and validation process to evaluate the CMTPedS. Based on the developmental phase of research, the CMTPedS is clinically meaningful, related to an explicit construct and easily interpretable. Based on the validation phase, the CMTPedS is a stable, reliable and psychometrically robust outcome measure for young children and adolescents with CMT to enable precise disease-relevant assessment. Based on the sensitivity analysis, the CMTPedS is highly sensitive to age and CMT type, generally not influenced by gender, and clearly reflects the severity of the disease.
There are no other measurement scales for children with CMT. The CMTNS, which has been validated in adults,49
has limited application in children because only four of nine items are regarded as sensitive.10
There are few scales in the neuropathy field,18,51
and none in the inherited neuropathies, validated with modern psychometric methods. Rasch has become the preferential method of validation. The Rasch model focuses on the probability of individuals scoring on an item correctly given their responses to other items in the scale (‘fit’). Within the framework of Rasch, the scale should work the same way, irrespective of the group being assessed (e.g. items should behave similarly independent of age, gender or diagnosis grouping).20
Rasch analysis supported the viability of the 11-item CMTPedS as a unidimensional measure of disability in children with CMT. It showed good overall model fit, no evidence of misfitting items, no person misfit, ability to differentiate groups of patients, no differential item functioning and it was well targeted for children with CMT.
There is international support for the CMTPedS to be implemented as the primary outcome measure in studies of children with CMT.8
The CMTPedS was designed to supplement a thorough neurological examination and capture functionally relevant limitations caused by CMT in the pediatric population. It is intended to have broad application in natural history studies and clinical trials of rehabilitative (e.g. orthoses, stretching, strengthening), pharmacological (e.g. curcumin, anti-progesterone) and surgical (e.g. foot and hand tendon transfer, arthodesis, hip dysplasia) interventions. At this stage, and by design, the CMTPedS is limited to children. However because it is based on activities that are relevant to daily life, there will be a demand to broaden the application of the CMTPedS to enable long term studies into adulthood to ensure consistent measurement across the lifespan of patient’s with CMT.
This study is primarily based on a cross-sectional analysis. In the future, 5-year follow-up data will be available through the Inherited Neuropathies Consortium to determine the longitudinal responsiveness and minimal clinically important difference of the CMTPedS. These data will demonstrate how large a change in CMTPedS points would be regarded by patients, parents and clinicians as indicating a meaningful improvement in day-to-day function following an experimental intervention. Different subtypes of CMT vary in severity and rate of progression. For instance, CMT1A, the most common form of CMT, is thought to progress quite slowly during childhood while patients with CMT2A are wheelchair bound by 21 years. Therefore, as suggested by our preliminary longitudinal data, it is likely that the rate of change of CMTPedS will vary, depending on the CMT subtype. To determine this experimentally will undoubtedly require larger numbers of children with different subtypes assessed longitudinally for 2-5 years, as we propose to do within our Consortium. Furthermore, even within subtype, patient to patient variability will influence the rate of change of the CMTPedS. For instance, the preliminary longitudinal data revealed five cases of CMT1A that showed an improvement on the CMTPedS while the other six cases of CMT1A did not. This accurately reflects the well-known heterogeneity of the disease, particular during childhood where rapid periods of growth and development can produce a variable clinical presentation and rate of progression.
Indeed, results from our 1-year placebo-controlled clinical trial of ascorbic acid for 81 children with CMT1A showed some cases of marked improvement in strength and motor function equally in both the treatment and control group.4
While the CMTPedS was not utilized in this trial as an outcome measure, the fundamental components of strength and motor function are common elements and illustrate the point of variability in patient response during childhood growth and development. The implications of this phenotypic variability on future clinical trial design requires larger samples to increase power and longer follow-up duration to account for natural growth fluctuations.
In conclusion, the final 11-item CMTPedS is a well-tolerated outcome measure that can be completed in 25 minutes. It generates a normally distributed score ranging from 0 to 44 points which is a reliable, valid and sensitive measure of disability for children with CMT from the age of 3 years.