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Magnetic resonance imaging as a surrogate outcome for multiple sclerosis relapses

¹ Department of Statistics, University of British Columbia, Vancouver, BC, Canada
² Scientific and Clinical Review Associates, LLC and National Multiple Sclerosis Society, New York City, NY, USA
³ Horton Centre for Patient-Oriented Research, University Hospital, Zurich, Switzerland (previously at The Sylvia Lawry Centre for Multiple Sclerosis Research, Munich, Germany)
⁴ Department of Biostatistics, University of Alabama at Birmingham, AL, USA
⁵ Biostatistics Department, University of Washington, Seattle, WA, USA
⁶ Harvard School of Public Health, Boston, MA, USA
⁷ NMR Research Unit, Institute of Neurology, London, UK
⁸ Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
⁹ Department of Neurology, University of Texas Health Sciences Center, Houston, TX, USA

^* To whom correspondence should be addressed.

	Abstract

Background

Magnetic resonance imaging (MRI) of lesions in the brain may be the best current candidate for a surrogate biological marker of clinical outcomes in relapsing remitting multiple sclerosis (MS), based on its role as an objective indicator of disease pathology. No biological surrogate marker has yet been validated for MS clinical outcomes.

Objective

The objective of this study was to use a multi-phased study to determine if a valid surrogate relationship could be demonstrated between counts of contrast enhancing lesions (CELs) and occurrence of relapses in MS.

Methods

We examined correlations for the concurrent and predictive relationship between CELs over 6 months and MS relapses over the same 6 months and an additional 6 months (total: 12 months), using available data on untreated patients from a large clinical trial and natural history database.

Results

Concurrent and predictive correlations were inadequate to justify continuation of this study to the planned additional phases required to demonstrate a surrogate relationship between CELs and MS relapses.

Conclusions

Confidence intervals for correlations between CELs and MS relapses exclude the possibility that CELs can be a good surrogate for relapses over the time scales we investigated. Further exploration of surrogacy between MRI measures and MS clinical outcomes may require improved datasets, the development of MRI techniques that couple better to clinical disease, and the ability to test a wide range of imaging- and clinically-based hypotheses for surrogacy.

Key Words: multiple sclerosis, magnetic resonance imaging, gadolinium enhanced lesions, surrogacy, prognosis, correlations

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