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. 2026 Jan;41(1):43-53.
doi: 10.1177/08830738251346348. Epub 2025 Jun 17.

Convergent Validity of the Fine Motor, Speech, and Cognitive Domains of the 5-Domain Niemann-Pick Disease Type C Clinical Severity Scale

Cristan Farmer  1 , Monica Lewis  2 , Nicole Farhat  3 , Kendall P Robbins  2 , Lisa Joseph  1 , Orsolya K Albert  2 , Simona Bianconi  3 , Anne Hoffmann  2 , Ivy Giserman-Kiss  1 , Derek M Alexander  3 , Audrey Thurm  1 , Forbes D Porter  3 , Elizabeth Berry Kravis  2
Affiliations

Convergent Validity of the Fine Motor, Speech, and Cognitive Domains of the 5-Domain Niemann-Pick Disease Type C Clinical Severity Scale

Cristan Farmer et al. J Child Neurol. 2026 Jan.

Abstract

The 5-Domain Niemann Pick Type C Clinical Severity Scale (5DNPCCSS) is used in clinical practice and trials. Although psychometric data support the clinical meaningfulness of the concepts and the scale's interrater reliability, more information is needed to support its construct validity. Here, we evaluated the convergent validity of the Cognition, Speech, and Fine Motor domains. Data from 121 individuals with Niemann-Pick disease type C were drawn from several studies conducted at 2 US sites. Direct standardized assessments included the Nine-Hole pegboard or Purdue pegboard, a portion of the Clinical Evaluation of Language Fundamentals, and the age-appropriate Wechsler IQ test or the Mullen Scales of Early Learning. The 5DNPCCSS domains were significantly related in the expected directions to their respective direct assessments, supporting their construct validity. In combination with previous evidence presented for the Ambulation and Swallow domains, these results support the fitness of purpose of the (5DNPCCSS for clinical studies in Niemann-Pick disease type C. ClinicalTrials.gov: NCT00344331, NCT01747135, NCT02534844.

Keywords: NPCCSS; Niemann-Pick type C; clinical outcome assessment; validity.

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Conflict of interest statement

Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Drs Farmer, Joseph, Giserman-Kiss, and Thurm declare no conflicts of interest. Dr Berry-Kravis has received funding from Acadia, Alcobra, AMO, Asuragen, Avexis, Biogen, BioMarin, Cydan, Engrail, Erydel, Fulcrum, GeneTx, GW, Healx, Ionis, Jaguar, Kisbee, Lumos, Marinus, Mazhi, Moment Biosciences, Neuren, Neurogene, Neurotrope, Novartis, Orphazyme/Kempharm/Zevra, Ovid, PTC Therapeutics, Retrophin, Roche, Seaside Therapeutics, Taysha, Tetra, Ultragenyx, Yamo, Zynerba, and Vtesse/Sucampo/Mallinckrodt Pharmaceuticals, to consult on trial design or run clinical or lab validation trials in genetic neurodevelopmental or neurodegenerative disorders, all of which is directed to Rush University Medical Center (RUMC) in support of rare disease programs; Dr Berry-Kravis receives no personal funds and RUMC has no relevant financial interest in any of the commercial entities listed. Dr Porter's research group has received support as part of a Cooperative Research and Development Agreement between NICHD, NIH, and Vtesse/Sucampo/Mallinckrodt/Mandos to facilitate the development of 2-hydroxypropyl-β-cyclodextrin for the treatment of individuals with Niemann-Pick disease type C.

Figures

Figure 1.
Figure 1.. Relationship between Wechsler IQ and 5DNPCCSS Cognition Rating at baseline (n=60).
Note: IQ = intelligence quotient. Using the first available assessment from each person, their nonverbal IQ (left) and verbal IQ (right) were plotted against their transformed 5DNPCCSS Cognition Score (see Table 1). The color of the point indicates the test used (WAIS = Wechsler Adult Intelligence Scale; WISC = Wechsler Intelligence Scales for Children; WPPSI = Wechsler Preschool and Primary Scales of Intelligence). The population mean for IQ is 100 and the standard deviation is 15. The dotted lines at 100 and 70 show the population mean and two standard deviations below the mean, respectively. A small amount of horizontal jitter was added to the data to reduce overplotting.
Figure 2.
Figure 2.. Relationship between Mullen DQ and 5DNPCCSS Cognition Rating at baseline (n=36).
Note: DQ = developmental quotient (ratio of mental age to chronological age). The nonverbal (left) and verbal (right) DQ from the Mullen for each person was plotted against their transformed 5DNPCCSS Cognition Score (see Table 1). DQs have no population distribution but are often interpreted in the same way as intelligence quotients (IQ). The population distribution of IQ is 100±15, and the dotted lines in the plot correspond to the average IQ and two standard deviations below average. A small amount of horizontal jitter was added to the data to reduce overplotting. All Mullens included in the analysis were administered in age-range.
See this image and copyright information in PMC

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