Validity and Reliability of Clinical and Patient-Reported Outcomes in Multisystem Proteinopathy 1

Abstract

Objective: Valosin-containing protein (VCP)-associated multisystem proteinopathy 1 (MSP1) is caused by variants in the VCP gene. MSP1 results in various phenotypes including progressive myopathy, Paget's disease of bone, frontotemporal dementia, amyotrophic lateral sclerosis, and parkinsonism, among others. Our study aimed to validate functional clinical outcome assessments (COA) and patient-reported outcomes (PRO) to inform clinical care practices and future clinical trial design. In addition, we evaluated the test-retest reliability of these COAs within clinics and remote environments.

Methods: Patients completed a battery of COA and PRO across a 2-day traditional onsite visit and a 2-day remote visit within their home environment. All COA and PRO deemed safe and feasible to complete based on participants' level of function and/or home environment were collected at each visit.

Results: Forty-six total patients enrolled in our study, 34 in our full study and 12 in an expanded remote-only cohort. Functional COA measured decline over reported disease duration in this cross-sectional group and significantly correlated with PRO (rho > 0.5, p < 0.001). Differences in lower and upper extremity involvement were noted across variant groups. Performance of functional COA was reliable and safe within and across onsite and remote testing environments (ICC > 0.7, p < 0.001).

Interpretation: Functional COA and PRO are valid and reliable to measure abilities in participants with MSP1. Testing can be completed reliably within the home, which could expand equitable access to clinical care and/or future clinical trial participation. Prospective longitudinal data collection is ongoing to understand outcome sensitivity and meaningful change over time.

Keywords: VCP‐associated multisystem proteinopathy; function; natural history.

FIGURE 1

Cross‐sectional performance of clinical outcome assessments (COA) by reported disease duration (first reported symptom) in years. (A) Individual performance of 100‐m timed test velocity with dotted lines at 4.0 m/s (i.e., running speed), 1.2 m/s (i.e., lower limit of functional community walking speed), and 0.8 m/s (i.e., lower limit of household walking speed); (B) performance of NSAD; (C) timed up and go (TUG); and (D) performance of upper limb (PUL) across the cohort.

FIGURE 2

Functional groupings of (A) NSAD score in ambulatory patients with valid TTR time (circles), without the ability to perform TTR (squares), and nonambulatory participants (triangles); and (B) PUL score in those with the strength to reach overhead (circles), perform mid‐level activities like bringing hand to mouth (squares), and those independently completing tabletop activities only (triangles).

FIGURE 3

Cross‐sectional performance of (A) NSAD, (B) 10 m velocity (dotted lines: 1.2 m/s lower limit of community walking speed; 0.8 m/s household walking speed), (C) PUL, (D) FVC percent of predicted (dotted lines: 70% as lower limit of normal performance; 50% as need for nocturnal ventilatory support) plotted by disease duration (years since first reported symptom) and variant group: p.Arg93Cys (red circles), p.Arg155Cys (green circles), p.Arg155His (green squares), p.Arg159Cys (blue circles), p.Arg159His (blue squares), and all other variants (black circles).

FIGURE 4

Bland–Altman plots to assess individual test–retest reliability of the (A) TUG at onsite visits, compared to (B) TUG across onsite and remote environments; and (C) PUL at remote visits, compared to (D) PUL across onsite and remote environments.