The findings of this study confirm the reliability and validity of this version of the WURS and suggest that it may be useful as a tool for assessing severity across neurological, physical and behavioral domains in WFS. The WURS demonstrates good inter-rater reliability and internal consistency, supporting the potential utility of the WURS across both clinical and research settings, including clinical trials. Content and concurrent validity were acceptable, as indicated by the high S-CVI values and Spearman’s rho. This demonstrates that the current version of the WURS is an accurate measure of many of the key neurological aspects of WFS. In addition to concurrent validity, we also found that the WURS had good predictive validity, in that it correlated with overall quality of life. Quality of life is considered to be the most important indicator of health outcomes in clinical practice and research. It is also considered by the FDA to be the most relevant outcome measure for clinical trials
[18, 22, 23]. Thus, these preliminary data suggest that the WURS is capturing aspects of the disease that are important to an individual’s daily life and well-being.
The selective nature of the correlations between WURS scales and conceptually similar standardized measures also suggested that the Physical and Behavioral scales capture qualitatively different constructs. For instance, the WURS Physical Assessment correlated highly with physical and neurological measures, but had low correlations with psychiatric measures. The WURS Behavioral Assessment demonstrated high correlations with measures of mood and behavior, and low correlations with physical and neurological assessments.
Furthermore, results suggest that there is variability within WFS for each construct that may be important to capture. For example, some aspects of WFS may progress at a different rate than others, or be differentially responsive to treatment. Thus, having valid, reliable measurement tools for these different constructs may be highly clinically relevant
. Longitudinal follow-up of this cohort and a larger, more diverse sample will be necessary to determine whether this is true.
The WURS appears to be sensitive to relatively mild stages of WFS. Our sample was small and tended to be in the early stages of the disease, but still had some variation in duration and severity of symptoms. The WURS captured this variability, distinguishing between mild and moderate levels of severity. For instance, the range of scores on the WURS Behavioral assessment (0 to 14 out of a possible 54) indicated that the individuals tested had relatively subtle behavioral issues. Yet, these scores correlated with ratings on the CBCL and SCAS, which placed the majority of participants within the normal range according to published norms. The mild levels of severity of all assessments of mood and behavior, in addition to the significant correlations between these measures, demonstrate that the WURS Behavioral Assessment is a sensitive measure of mood and behavior problems. The Mini-BESTest and PANESS, measures of physical and neurological impairment, also correlated highly with the WURS Physical Scale. Scores on these assessments demonstrated low to moderate levels of impairment indicating that this domain is also an accurate and sensitive measure of physical impairment.
There are several limitations of this study, including the small sample size, which is not uncommon in clinical research studies of rare disease. Continued research in this population across research centers, clinics and countries using standardized assessments such as the WURS will be necessary to draw stronger conclusions. Given the now promising validity and reliability of the WURS, we are now starting to establish such collaborations. In addition, time constraints limited us from having both WURS raters independently administer and score the WURS. To eliminate potential of bias by having both raters in the same room, future studies should implement independent administration and scoring of the WURS. Despite this limitation, our method does allow the conclusion that the current version of the WURS can be used consistently across individuals when they are provided with the same information.
Future modifications of the WURS are possible. For example, the WURS currently lacks some reported symptoms of WFS, including dysphagia, gag reflex impairment, peripheral and autonomic neuropathy, and cranial nerve involvement
[24, 25]. These items could be added to the WURS Physical Assessment, which may be particularly useful with more severely affected cohorts. Notably, there is a part of the WURS that allows for symptoms not listed to be noted by the rater. In our sample, none of these symptoms were noted. The WURS also includes items from the UBDRS that are not as widely recognized as common WFS symptoms. At this stage of the WURS development, we decided to keep all items from the UBDRS because they were psychometrically sound, and we could not be sure that the items would not be useful in more severely affected patients. With greater use of the WURS across time, a wider range of age and severity levels, we will be able to perform item specific analyses and drop items that have no added value for assessing disease severity and change over time. Finally, with the exception of the WFS History section, diabetes-related symptoms are not specifically addressed in the WURS. It is thought that these symptoms are not degenerative after diagnosis, unlike those of the neurological aspects of disease. However, exploration of diabetes-related symptoms may be necessary for a better understanding of diabetes treatment issues. Appropriateness of diabetes related items will be considered for the WURS once further examination is completed. Importantly, there are existing validated questionnaires for diabetes complications, management and quality of life that could be used as adjunct measures to the WURS if desired
[26–29]. Similarly, cognitive testing is not currently incorporated into the WURS. While cognitive impairment has been reported in advanced WFS, it has not been found with standard assessments in our small sample of early WFS patients
. Further assessment will determine if cognitive items should be added to the WURS, or if the result of a supplementary cognitive test should be reflected in the WURS scoring.
Although neurologists are currently the primary clinicians using the assessment, it is hoped that other health care practitioners will be able to administer the WURS effectively. A training video will be developed in the future. We will investigate the minimum amount of training necessary for neurologists or other health professionals to administer the WURS. The UPDRS and other similar ratings scales are typically given by a variety of health professionals and technicians, who follow standardized training.
In summary, the preliminary data presented here support the use of the WURS in studies of WFS as a reliable and valid measurement tool for disease severity. The scale will continue to be developed as we are able to test a larger and more diverse sample. Further development and analyses of the WURS will be important for continued research of WFS in order to better understand symptoms and progression of the disease, in addition to its eventual use in clinical trials for therapeutic interventions.