Sola-Valls_et_al._supplementary_table_1 – Supplemental material for Combined walking outcome measures identify clinically meaningful response to prolonged-release fampridine

<p>Supplemental material, Sola-Valls_et_al._supplementary_table_1 for Combined walking outcome measures identify clinically meaningful response to prolonged-release fampridine by Núria Sola-Valls, Yolanda Blanco, María Sepúlveda, Sara Llufriu, Elena H. Martínez-Lapiscina, Irati Zubizarreta, Irene Pulido-Valdeolivas, Carmen Montejo, Pablo Villoslada and Albert Saiz in Therapeutic Advances in Neurological Disorders</p

The MS Ontology.

<p>A) Basic formal ontology integration of MS Ontology; B) Extracted views of the MS Ontology showing the hierarchy of the concepts; C) Source documents for each category used for creating the ontology.</p

Results of competency questions evaluation using MS Ontology compared to manual search on PubMed.

<p>Results are shown as the number of all retrieved documents and the “validated ones” based in manual review of the documents by the expert in order to ensure they were covering the topics of the competency questions. We define as the gold standard for calculating sensitivity, the expert search in PubMed using key words (related with AND) and the manual revision of the abstracts. In order to calculate ‘Sensitivity’ and ‘Specificity’ of MS Ontology based searches, true positives are defined as the number of ‘validated documents’ retrieved by a MS Ontology based search; false positive are the number of documents retrieved by MS Ontology based search but were not considered relevant in expert review and False negatives are the number of documents retrieved by ‘expert based searches’ in PubMed but were not retrieved by MS Ontology. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116718#pone.0116718.s001" target="_blank">S1 Methods</a> for details of the searches.</p><p>Results of competency questions evaluation using MS Ontology compared to manual search on PubMed.</p

Concepts identified using the MS Ontology in the competency questions.

<p>Figure shows the concepts (in grey boxes) retrieved in the competency questions (search strategy) annotated by the MS Ontology and linked to other MS Ontology concepts, indicating the PMID of the abstract from PubMed and the type of interaction described in such abstract. A) references linking brain atrophy and CNS repair with remyelination in MS; B) references linking Myelin Oligodendrocyte Glycoprotein (MOG) to antibody-mediated demyelination; and C) references linking fingolimod tested as a drug for treatment of relapsing-remitting MS in phase 3 clinical trials</p

Analysis of the distribution of the EDSS time series.

<p>A) Distribution of the time intervals between the clinical relapses. The distribution is derived from the experimental data of the EDSS time series (orange), simulations from the ODE model of T cell cross-regulation [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005757#pcbi.1005757.ref004" target="_blank">4</a>] (light blue) and the results from the GEV distribution model (red line). B-C) Examples of the analysis of the EDSS time-series in patients with MS. Incremental changes in EDSS over time in the experimental series for (B) PPMS and (C) SPMS. The onset of ΔEDSS is marked with an asterisk.</p

The ODE model of CNS damage in MS.

<p>A) The model represents the volume occupied by axons and myelin: Right, the healthy CNS is composed of myelinated axons (<i>A</i>_<i>m</i>); Center, inflammatory attack is represented by the time-dependent parameter λ(t), which arises from the Generalized Extreme Value (GEV) distribution of the EDSS time-series, producing either demyelination (right) or degeneration of axons (bottom); Left, demyelinated axons (<i>A</i>_<i>d</i>) can be remyelinated with myelin produced by oligodendrocytes (<i>M)</i>, as a function of the parameters <i>km</i> and <i>q</i>; Bottom, myelinated or demyelinated axons can be lost by either acute axon transection or degeneration (<i>D)</i>, according to the parameters <i>kmd</i> or <i>kd</i> respectively. B) Clustering MS patients based on the EDSS time series. The horizontal axes correspond to the time in months (maximum = 16 months), while the vertical axes correspond to the patients. Each line represents the EDSS of a given patient over time, using a color scale to reflect the EDSS. Clusters 1 and 2 include patients that maintain an intermediate short term EDSS and that reach a high EDSS in the long term. Cluster 3 includes patients that maintain a low short term EDSS and that achieve an intermediate EDSS in the long term. Cluster 4 represents a more heterogeneous group.</p

Comorbidities diagnosed in patients with MS identified in the EMR.

<p>Comorbidities diagnosed in patients with MS identified in the EMR.</p

The distribution of the model’s parameters calculated for the four clusters.

<p>Each boxplot shows the distribution of each parameter in the model for each of the clusters: <i>km</i>, <i>kmd</i>, <i>kd</i>, <i>q</i>, and <i>δ</i>.</p

Dynamics of the clinical and pathogenic processes in MS.

<p>The upper panel shows the evolution of relapsing-remitting MS (RRMS) and its transition to secondary-progressive MS (SPMS), while the bottom panel shows the evolution of primary-progressive MS (PPMS). The autoimmune process starts in the peripheral immune system, inducing episodes of CNS inflammation (red line) that subsequently provokes demyelination (blue line) and then axon degeneration (dark green line). Although inflammation and demyelination may experience remissions, axon degeneration accumulates over time, as does chronic compartmentalized inflammation (orange line). If inflammatory infiltrates affect eloquent CNS regions and exceed damage thresholds, they manifest as clinical relapses. Alternatively, when cumulative axon degeneration surpasses the capacity of the functional CNS reserve, permanent neurological disability arises (light blue line) and there is a transition to the progressive disease. The decrease in brain volume over time is more severe at the beginning of the disease, in parallel with more intense inflammatory activity, and it continues steadily as the disease evolves. PPMS follows the same processes but the inflammatory relapses are not translated into clinical relapses, either because they are less frequent, less severe or they affect silent (non-eloquent) areas. Only when axon degeneration reaches a clinical threshold is disability manifested as progressive. Therefore, there are no differences between SPMS and PPMS except for the relative clinical impact (relapses) of acute inflammatory activity.</p

Top 5-drug usage by patients with MS identified in the EMR.

<p>Top 5-drug usage by patients with MS identified in the EMR.</p