Cognitive endpoints for therapy development for neuronopathic mucopolysaccharidoses: Results of a consensus procedure

The results of a consensus meeting of 15 international experts on cognitive endpoints in MPS has just been published. A modified Delphi technique was used. Briefly this is a systematic forecasting method that involves structured interaction among a group of experts on a subject. It typically includes at least two rounds of experts answering questions and giving justification for their answers, providing the opportunity between rounds for changes and revisions. The multiple rounds, which are stopped after a pre-defined criterion is reached, enable the group of experts to arrive at a consensus forecast on the subject being discussed.

There was a very high level of consensus. Of the 12 statements considered, there was 93% consensus on 11 and 100% consensus on the other 11.

This a very timely paper in view of the increasing number of clinical trials, both in progress and being planned, for the neuronopathic forms of MPS disorders, and the plethora of assessment tools currently available.

The statements are given below (copied directly from the paper). For those who are interested in further details, here is the link to the full paper. 

For trials evaluating the effect of treatment in children with MPS I, II or III aged up to 3years (age equivalent), the recommended instrument to measure cognitive outcomes is the Bayley-III.

For trials evaluating the effect of treatment in children with MPS I, II or III of all ages, the recommended instrument to measure adaptive behavior is the Vineland, using the extended interview format.

For (multinational) trials evaluating the effect of treatment in children with MPS I aged 3years and over (age equivalent), the recommended instruments to measure cognitive outcome are the Wechsler tests. We recognize the utility of the Kaufman Assessment Battery for Children, Second Edition (KABC-II) and the Differential Ability Scales, Second Edition (DAS-II) in particular populations because of their reduced fine motor demand and less emphasis on speed of performance compared with the Wechsler tests.

For (multinational) trials evaluating the effect of treatment in children with MPS II or III aged 3–18years (age equivalent), the recommended instruments to measure cognitive outcome are either the DAS-II or the KABC-II. The use of only the non-verbal domain/index may be appropriate if this is necessary to ensure consistent application between trial sites across multiple countries. Other factors to consider in the selection of the measure and on whether to use the entire test or only the non-verbal domain are: the need for verbal interaction; the time required to administer the test; fine motor requirements; availability of normative data; availability of translations.

In a set of trials within the same program, we recommend using the same test protocol for all trial sites worldwide; including, if possible, the same test editions or, if not, the most recent.

We acknowledge the usefulness and value of historical data that elucidate the natural history of MPS I, II and III, including standardized cognitive and developmental outcome measures other than those recommended in these consensus statements.

We strongly recommend building and sustaining an infrastructure to share natural history data.

We acknowledge that in multinational trials it may be necessary and appropriate to use one set of psychometrically sound normative data; however, this is only recommended for a non-verbal outcome measure. If a specified tool has not been validated in a country, we recommend the parallel use of a country-specific instrument to establish concurrent validity.

We recommend the use of a standard written translation of the measurement instrument, including the administration instructions, produced by a professional translator with experience with standardized tests. Such a professional translation should always be accompanied by a back-translation. We also recommend cross-cultural adaptation. Lastly, we recommend that a local psychologist/psychometrician should review the fidelity of the translation and of the cross-cultural adaptation.

Assessors must be qualified in administering neurodevelopmental measurement instruments and have experience in their use, preferably with the disease being evaluated. Assessors need to be trained in person to perform the specific measurements in the protocol and should be subject to periodic quality control and auditing of scoring.

We recommend analyzing and reporting age-equivalent scores in all trials, and standard scores where possible.

When transitioning from one test to another because of developmental or chronological age, we recommend administering the two tests concurrently at least once during the same visit (on separate days) to compare the test results.

As far as I am aware, this is the first time a consensus paper on this important subject has been written. The authors make the point that new assessment tools are likely to be published in the future, and stress the importance of reviewing and, if necessary, revising these recommendations every 3 years.

Author: Ashok Vellodi

I have had a lifelong interest in lysosomal storage disorders. Having recently retired I now have time to pursue my passion for teaching and training of young doctors and scientists, and hopefully instil in them the passion for their patients that is so integral to working in this field.

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