@article {zhao_personalized_2015,
	title = {Personalized activity index, a new safety monitoring tool for multiple sclerosis clinical trials},
	journal = {Multiple Sclerosis Journal {\textendash} Experimental, Translational and Clinical},
	volume = {1},
	year = {2015},
	pages = {1-15},
	abstract = {<p>Background An abnormal increase of contrast-enhancing lesion (CEL) counts on frequent MRIs is interpreted as a signal of potential worsening in multiple sclerosis (MS) clinical trials. We demonstrate the utility of the MR personalized activity index (MR-pax) to identify such increases. Methods We analyzed a previous Phase II study in relapsing patients (n = 167) with MRIs at screening, baseline and months 1{\textendash}6. We performed five consecutive reviews at 90-day intervals. At each review, we evaluate the MR-pax for each patient and also identify those who meet the rule-of-five (an ad-hoc guideline currently in use). To evaluate its clinical relevance, we assess the relation between having a small MR-pax (<=0.05; indicating an unexpected CEL increase) and relapse status in the 12 weeks post-review. Results Of the 399 patient reviews, 35 cases met the rule-of-five; 35 had an MR-pax <= 0.05; 18 met both criteria. The proportions experiencing clinical relapse are 63\% among those meeting the rule-of-five, 61\% among those with MR-pax <=0.05, and 83\% for those meeting both criteria, more than double the rate of those meeting neither criterion (40\%). Conclusion A guideline combining this new personalized index and the existing threshold-based criterion is able to better identify patients with a higher risk of experiencing relapses.</p>
},
	keywords = {contrast-enhancing lesions, MRI, multiple sclerosis, safety monitoring in clinical trials},
	doi = {10.1177/2055217315577829},
	url = {http://mso.sagepub.com/content/1/2055217315577829},
	author = {Zhao, Y and Kondo, Y and Traboulsee, A and Li, DKB and Riddehough, A and Petkau, A.John}
}
@article { ISI:000364161000010,
	title = {Sample-size calculations for short-term proof-of-concept studies of tissue protection and repair in multiple sclerosis lesions via conventional clinical imaging},
	journal = {Multiple Sclerosis Journal},
	volume = {21},
	number = {13},
	year = {2015},
	pages = {1693-1704},
	publisher = {SAGE PUBLICATIONS LTD},
	address = {1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND},
	abstract = {<p>Background: New multiple sclerosis (MS) lesion activity on magnetic resonance imaging (MRI) can test immunomodulatory therapies in proof-of-concept trials. Comparably powerful endpoints to assess tissue protection or repair are lacking. Objective: The objective of this paper is to report sample-size calculations for assessment of new lesion recovery. Methods: In two sets of six active MS cases, new lesions were observed by monthly MRI for approximately 12 months. Averages and quartiles of normalized (proton density/T1/T2 weighted) and quantitative (T1/T2 and mean diffusivity maps for dataset 1, T2 and magnetization transfer ratio maps for dataset 2) measures were used to compare the lesion area before lesion appearance to afterward. A linear mixed-effects model incorporating lesion- and participant-specific random effects estimated average levels and variance components for sample-size calculations. Results: In both datasets, greatest statistical sensitivity was observed for the 25th percentile of normalized proton density-weighted signal. At 3T, using new lesions 15 mm(3), as few as nine participants/arm may be required for a six-month placebo-controlled add-on trial postulating a therapeutic effect size of 20\% and statistical power of 90\%. Conclusion: Lesion recovery is a powerful outcome measure for proof-of-concept clinical trials of tissue protection and repair in MS. The trial design requires active cases and is therefore best implemented near disease onset.</p>
},
	keywords = {clinical trial design, MRI, repair, T2 lesions},
	doi = {10.1177/1352458515569098},
	author = {Reich, DS and White, R and Cortese, ICM and Vuolo, L and Shea, CD and Collins, TL and Petkau, J}
}
