Measuring Fatigue in Multiple Sclerosis: There may be Trouble Ahead

Area of Science:

• Clinical research methodology
• Psychometrics
• Neurology

Background:

• Poorly developed patient-reported outcome measures (PROs) can lead to false negatives in clinical trials.
• Content validity, determined by PRO items, is crucial for reliable measurement.
• Fatigue is a common and burdensome symptom in multiple sclerosis (MS).

Purpose of the Study:

• To identify fatigue PRO instruments used in MS studies.
• To evaluate the development of these PROs against current content validity standards.

Main Methods:

• Searched Embase and Medline for MS studies using fatigue-based PROs.
• Screened abstracts and identified PROs.
• Assessed PRO development against seven Consensus Standards for Measurement Instruments (COSMIN) criteria.

Main Results:

• 18 fatigue PROs were identified; most failed to meet at least one COSMIN content validity standard.
• Common omissions in PRO development included defined constructs, conceptual frameworks, and qualitative research.
• PRO development quality has improved since FDA guidance, but quality is unrelated to citation or trial usage.
• The Fatigue Symptoms and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) and Neurological Fatigue Index-Multiple Sclerosis (NFI-MS) showed the strongest evidence for content validity based on aggregate scores.

Conclusions:

• Most fatigue PROs in MS do not meet COSMIN content validity standards.
• Even well-scoring PROs like NFI-MS and FSIQ-RMS have limitations in content validity upon closer item evaluation.
• COSMIN criteria may need refinement, and current measurement of MS fatigue raises concerns.
• Further psychometric evaluation is needed to understand the impact of PRO development quality on measurement performance.