Utility of Progression Independent of Relapse Activity as a Trial Outcome in Relapsing-Remitting Multiple Sclerosis
Bibliographic record
Abstract
BACKGROUND AND OBJECTIVES: Progression independent of relapse activity (PIRA) is increasingly used as a measure of disability worsening in multiple sclerosis (MS) and is believed to reflect the more chronic neurodegenerative aspect of MS. However, while conceptually appealing, PIRA and its counterpart relapse-associated worsening (RAW) have not been validated as outcome measures for clinical trials. Here, we study the co-occurrence of MRI activity in patients experiencing PIRA and RAW in a clinical trial setting. To illustrate the problem of random variation and measurement error of these new outcomes, we contrasted PIRA and RAW with similarly defined improvement. METHODS: We reanalyzed individual patient-level data of AFFIRM (NCT00027300) and SENTINEL (NCT00030966), 2 multicenter randomized controlled trials investigating natalizumab compared with interferon beta or placebo in RRMS, with trial visits occurring every 3 months for 2 years. We calculated 3-month-confirmed disability worsening (3M-CDW), RAW, and PIRA events based on worsening on the Expanded Disability Status Scale, 9-hole peg test, or timed 25-foot walk for every trial visit. We related worsening and improvement events to MRI activity throughout follow-up and contrasted worsening of disability with similarly defined improvement. RESULTS: Our analysis included 2,113 participants, 42.4% of whom developed radiologic disease activity during follow-up. Only 8% of participants had a 3M-CDW event. Although the majority of those 3M-CDW events were PIRA (6.8%) and not RAW (0.9%), 42.2% of participants with PIRA had MRI activity in the first year of follow-up and 30.9% in the second. Improvement events exceeded PIRA events throughout follow-up and occurred in all trial arms. Finally, there was no difference in time-to-PIRA between participants with and without radiologic disease activity. DISCUSSION: PIRA and RAW in their current definitions do not reliably distinguish between disability worsening due to inflammatory disease activity and neurodegeneration in RRMS. In addition, PIRA and RAW have similar and troubling issues of random variation and measurement error as currently used trial outcome measures. Our analysis requires confirmation in other clinical data sets; a meaningful next step would be to study the co-occurrence of PIRA with radiologic disease activity in a setting with more comprehensive MRI monitoring.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.094 | 0.080 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.003 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".