Contributions
Abstract: P411
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Genetics /Epigenetics and Pharmacogenetics
Background: To-date efforts to identify genetic associations with MS phenotype have been largely unrewarding. One possible explanation for this is that past genotype-phenotype association studies have relied on cross-sectional definitions of disease severity.
Objective: To define a robust relapse-onset MS (RMS) disease severity phenotype based on longitudinally acquired outcomes data for use in genetic association studies.
Methods: Using data obtained from MSBase, we identified all RMS patients from collaborating centres with minimum disease duration of 5 years, 5 years minimum prospective follow-up, and minimum 3 EDSS scores recorded in the absence of a relapse. Collaborating physicians nominated mild and severe RMS patients from their centres that served to define cut-offs for phenotypic outcomes of interest. Area under the EDSS-time curve was calculated for each individual and adjusted for follow-up. Using pre-defined EDSS-time cut-offs we created an algorithm that identified patients at the clinician-defined extremes of RMS outcome. Our algorithm was relapse, MRI and treatment agnostic. We validated algorithm calls by assessment of median MSSS over the entire observation period.
Results: We identified 5,075 individuals meeting minimum inclusion criteria. Median cohort follow-up in MSBase was 8.8 years (interquartile range (IQR): 6.7y, 12.5y), with a median 16 (IQR: 9, 27) EDSS scores available for assessment. Median symptom duration at most recent visit was 15.2 years, and median MSSS over the entire observation period was 3.49 (IQR: 2.06, 5.51). The mild RMS cohort as selected by our algorithm (25.9% of the total population) had a median symptom duration of 11.6 years (IQR: 8.2, 16.5), 14 EDSS scores assessed (IQR: 8,25), and a median observation follow-up MSSS of 1.50 (IQR: 0.88, 2.25). The severe RMS cohort constituted 18.4% of the total population. Severe RMS cohort characteristics included: median symptom duration of 19.0 years (IQR: 13.5, 25.9), 15 EDSS scores assessed (IQR: 9, 24), and a median observation follow-up MSSS of 7.21 (6.15, 8.27).
Conclusion: We have successfully defined a robust RMS phenotype using longitudinal, prospectively acquired clinical outcomes data validated against the MSSS. We are now actively recruiting patients identified using this definition of disease severity to perform a de novo genome-wide association study aiming to identify markers of relapse-onset MS severity.
Disclosure: This study is supported by grants from The Royal Melbourne Hospital [MH2013-055]; The MSBase Foundation; CharityWorks for MS/MS Research Australia [MSRA12-062], and an NHMRC Centre for Research Excellence Grant [Grant ID 1001216]. The MSBase Foundation is an independent not for profit organisation which receives support in the form of grants from the National Health and Medical Research Council (NHMRC) Australia, Merck, Merck Serono, Biogen, Novartis, and Genzyme a Sanofi company.
The Authors report no disclosures with regards to this study.
VGJ: Nothing to disclose; TK: Nothing to disclose; DH: Nothing to disclose; EH: Nothing to disclose; PK: Nothing to disclose; KK: Nothing to disclose; GI: Nothing to disclose; FM: Nothing to disclose; AL: Nothing to disclose; TJK: Nothing to disclose; JLS: Nothing to disclose; MS: Nothing to disclose; SV: Nothing to disclose; DB: Nothing to disclose; AM: Nothing to disclose; BT: Nothing to disclose; JH: Nothing to disclose; PDJ: Nothing to disclose; HB Nothing to disclose.
Abstract: P411
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Genetics /Epigenetics and Pharmacogenetics
Background: To-date efforts to identify genetic associations with MS phenotype have been largely unrewarding. One possible explanation for this is that past genotype-phenotype association studies have relied on cross-sectional definitions of disease severity.
Objective: To define a robust relapse-onset MS (RMS) disease severity phenotype based on longitudinally acquired outcomes data for use in genetic association studies.
Methods: Using data obtained from MSBase, we identified all RMS patients from collaborating centres with minimum disease duration of 5 years, 5 years minimum prospective follow-up, and minimum 3 EDSS scores recorded in the absence of a relapse. Collaborating physicians nominated mild and severe RMS patients from their centres that served to define cut-offs for phenotypic outcomes of interest. Area under the EDSS-time curve was calculated for each individual and adjusted for follow-up. Using pre-defined EDSS-time cut-offs we created an algorithm that identified patients at the clinician-defined extremes of RMS outcome. Our algorithm was relapse, MRI and treatment agnostic. We validated algorithm calls by assessment of median MSSS over the entire observation period.
Results: We identified 5,075 individuals meeting minimum inclusion criteria. Median cohort follow-up in MSBase was 8.8 years (interquartile range (IQR): 6.7y, 12.5y), with a median 16 (IQR: 9, 27) EDSS scores available for assessment. Median symptom duration at most recent visit was 15.2 years, and median MSSS over the entire observation period was 3.49 (IQR: 2.06, 5.51). The mild RMS cohort as selected by our algorithm (25.9% of the total population) had a median symptom duration of 11.6 years (IQR: 8.2, 16.5), 14 EDSS scores assessed (IQR: 8,25), and a median observation follow-up MSSS of 1.50 (IQR: 0.88, 2.25). The severe RMS cohort constituted 18.4% of the total population. Severe RMS cohort characteristics included: median symptom duration of 19.0 years (IQR: 13.5, 25.9), 15 EDSS scores assessed (IQR: 9, 24), and a median observation follow-up MSSS of 7.21 (6.15, 8.27).
Conclusion: We have successfully defined a robust RMS phenotype using longitudinal, prospectively acquired clinical outcomes data validated against the MSSS. We are now actively recruiting patients identified using this definition of disease severity to perform a de novo genome-wide association study aiming to identify markers of relapse-onset MS severity.
Disclosure: This study is supported by grants from The Royal Melbourne Hospital [MH2013-055]; The MSBase Foundation; CharityWorks for MS/MS Research Australia [MSRA12-062], and an NHMRC Centre for Research Excellence Grant [Grant ID 1001216]. The MSBase Foundation is an independent not for profit organisation which receives support in the form of grants from the National Health and Medical Research Council (NHMRC) Australia, Merck, Merck Serono, Biogen, Novartis, and Genzyme a Sanofi company.
The Authors report no disclosures with regards to this study.
VGJ: Nothing to disclose; TK: Nothing to disclose; DH: Nothing to disclose; EH: Nothing to disclose; PK: Nothing to disclose; KK: Nothing to disclose; GI: Nothing to disclose; FM: Nothing to disclose; AL: Nothing to disclose; TJK: Nothing to disclose; JLS: Nothing to disclose; MS: Nothing to disclose; SV: Nothing to disclose; DB: Nothing to disclose; AM: Nothing to disclose; BT: Nothing to disclose; JH: Nothing to disclose; PDJ: Nothing to disclose; HB Nothing to disclose.