Abstract
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
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
| Original language | English |
|---|---|
| Article number | P411 |
| Pages (from-to) | 168-169 |
| Number of pages | 2 |
| Journal | Multiple Sclerosis |
| Volume | 22 |
| Issue number | 3: Suppl. |
| DOIs | |
| Publication status | Published - 2016 |
Keywords
- Multiple Sclerosis
- Phenotypes
- MS phenotype
- Patient outcomes