Measuring Fatigue in Multiple Sclerosis: There may be Trouble Ahead.

Abstract

Poorly developed patient-reported outcome measures (PROs) risk type-II errors (i.e. false negatives) in clinical trials, resulting in erroneous failure to achieve trial endpoints. Validity is a fundamental requirement of fit-for-purpose PROs, with the main determinant of validity being the PROs items, i.e. content validity. Here, we sought to identify fatigue PRO instruments used in multiple sclerosis (MS) studies and to assess the extent to which their development satisfied current content validity standards. We searched Embase® and Medline® for MS studies using fatigue-based PROs. Abstracts were screened, PROs identified, and their relevant development papers assessed against seven Consensus Standards for Measurement Instruments (COSMIN) criteria for content development. From 3814 abstracts, 18 fatigue PROs met our inclusion criteria. Most PROs did not satisfy at least one COSMIN content validity standard. Frequent omissions during PRO development include: clearly defined constructs; conceptual frameworks; qualitative research in representative samples; and literature reviews. PRO development quality has improved significantly since FDA guidance was published (U=10.0, p=0.02). However, scatterplots and correlations between PRO COSMIN scores and citation frequency (rho=-0.62) and clinical trials usage (rho=+0.18) implied that PRO quality is unrelated to choice. COSMIN scores implied that the Fatigue Symptoms and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) and Neurological Fatigue Index-Multiple Sclerosis (NFI-MS) had the strongest evidence for adequate content validity. Most existing fatigue PROs do not meet COSMIN content validity requirements. Although two PROs scored well on aggregate (NFI-MS and FSIQ-RMS), our subsequent evaluation of the item sets that generated their scores implied that both PROs have weaker content validity than COSMIN suggests. This indicates that COSMIN criteria require further development, and raises significant concerns about how we have measured one of the most common and burdensome MS symptoms. A detailed head-to-head psychometric evaluation is needed to determine the impact of different PRO development qualities and the implications of the problems implied by our analyses, on measurement performance.