Browsing by Author "Tapia-Maltos, Marco Aurelio"

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Meta-analysis of the Age-Dependent Efficacy of Multiple Sclerosis Treatments
(2017-11) Weideman, Ann Marie; Tapia-Maltos, Marco Aurelio; Johnson, Kory; Greenwood, Mark C.; Bielekova, Bibiana
Objective: To perform a meta-analysis of randomized, blinded, multiple sclerosis (MS) clinical trials, to test the hypothesis that efficacy of immunomodulatory disease-modifying therapies (DMTs) on MS disability progression is strongly dependent on age. Methods: We performed a literature search with pre-defined criteria and extracted relevant features from 38 clinical trials that assessed efficacy of DMTs on disability progression. We fit a linear regression, weighted for trial sample size, and duration, to examine the hypothesis that age has a defining effect on the therapeutic efficacy of immunomodulatory DMTs. Results: More than 28,000 MS subjects participating in trials of 13 categories of immunomodulatory drugs are included in the meta-analysis. The efficacy of immunomodulatory DMTs on MS disability strongly decreased with advancing age (R-2= 0.6757, p = 6.39e-09). Inclusion of baseline EDSS did not significantly improve the model. The regression predicts zero efficacy beyond approximately age 53 years. The comparative efficacy rank derived from the regression residuals differentiates high-and low-efficacy drugs. High-efficacy drugs outperform low-efficacy drugs in inhibiting MS disability only for patients younger than 40.5 years. Conclusion: The meta-analysis supports the notion that progressive MS is simply a later stage of the MS disease process and that age is an essential modifier of a drug efficacy. Higher efficacy treatments exert their benefit over lower efficacy treatments only during early stages of MS, and, after age 53, the model suggests that there is no predicted benefit to receiving immunomodulatory DMTs for the average MS patient.
New Multiple Sclerosis Disease Severity Scale Predicts Future Accumulation of Disability
(2017-11) Weideman, Ann Marie; Barbour, Christopher; Tapia-Maltos, Marco Aurelio; Tran, Tan; Jackson, Kayla; Kosa, Peter; Komori, Mika; Wichman, Alison; Johnson, Kory; Greenwood, Mark C.; Bielekova, Bibiana
The search for the genetic foundation of multiple sclerosis (MS) severity remains elusive. It is, in fact, controversial whether MS severity is a stable feature that predicts future disability progression. If MS severity is not stable, it is unlikely that genotype decisively determines disability progression. An alternative explanation tested here is that the apparent instability of MS severity is caused by inaccuracies of its current measurement. We applied statistical learning techniques to a 902 patient-years longitudinal cohort of MS patients, divided into training (n = 133) and validation (n = 68) sub-cohorts, to test four hypotheses: (1) there is intra-individual stability in the rate of accumulation of MS-related disability, which is also influenced by extrinsic factors. (2) Previous results from observational studies are negatively affected by the insensitive nature of the Expanded Disability Status Scale (EDSS). The EDSS-based MS Severity Score (MSSS) is further disadvantaged by the inability to reliably measure MS onset and, consequently, disease duration (DD). (3) Replacing EDSS with a sensitive scale, i.e., Combinatorial Weight-Adjusted Disability Score (CombiWISE), and substituting age for DD will significantly improve predictions of future accumulation of disability. (4) Adjusting measured disability for the efficacy of administered therapies and other relevant external features will further strengthen predictions of future MS course. The result is a MS disease severity scale (MS-DSS) derived by conceptual advancements of MSSS and a statistical learning method called gradient boosting machines (GBM). MS-DSS greatly outperforms MSSS and the recently developed Age Related MS Severity Score in predicting future disability progression. In an independent validation cohort, MS-DSS measured at the first clinic visit correlated significantly with subsequent therapy-adjusted progression slopes (r = 0.5448, p = 1.56e-06) measured by CombiWISE. To facilitate widespread use of MS-DSS, we developed a free, interactive web application that calculates all aspects of MS-DSS and its contributing scales from user-provided raw data. MS-DSS represents a much-needed tool for genotype-phenotype correlations, for identifying biological processes that underlie MS progression, and for aiding therapeutic decisions.