SPINCOMS Biomarker Study

Study Overview
=================
Brief Summary
-----------------
To determine if biomarker-based CSF testing is reliably detecting differences between patients with Multiple Sclerosis (MS), different MS-subtypes, and other central nervous system (CNS) diseases. This study will also look to identify biomarkers that could be used for the prediction, at the time of diagnosis, of the future disease clinical course and response to therapy. The SOMAscan assay will be used for CSF samples analysis.

Detailed Description
-----------------
Using machine learning, the investigators have developed from SOMAScan: A molecular diagnostic test that differentiates MS from other inflammatory and non-inflammatory central nervous system (CNS) diseases (area under receiver-operator characteristic curve-AUROC of 0.98); A molecular test that differentiates relapsing-remitting MS from progressive MS variants (AUROC of 0.91); and A molecular test that predicts future rates of disability progression, concordance coefficient of 0.425 (p<0.001). Because these results are derived from a single research center (NIAID/NDS), it is imperative to determine their performance in real clinical practice settings as a necessary step for their potential regulatory approval. Consequently, this application has 2 specific aims: AIM 1. To independently validate afore-mentioned CSF-biomarker-based tests for their clinical value within the multicenter Spinal fluid Consortium for MS (SPINCOMS). In Aim 1, each of the 3 defined tests will be validated in 100 new SPINCOMS patients. To validate the prognostic test, 100 MS patients with CSF collected at least 3 years ago will be evaluated at follow-up examination with standardized clinical outcomes. CSF will be analyzed blinded using pre-defined statistical models. AIM 2. To explore whether collected CSF-biomarkers point towards pathogenic heterogeneity that may predict patient-specific efficacy for different disease-modifying treatments (DMTs) or identify pathogenic mechanisms not targeted by current DMTs. In Aim 2, clustering analysis will assess pathogenic heterogeneity and explore potential predictors of response to therapy.

Official Title
-----------------
Cerebrospinal Fluid-biomarkers-based Diagnostic and Prognostic Models for Multiple Sclerosis

Conditions
-----------------
Multiple Sclerosis

Intervention / Treatment
-----------------
* Device: SOMAscan


Participation Criteria
=================
Eligibility Criteria
-----------------
MS Patients selection criteria Lumbar puncture (LP) in the untreated stage with cryopreserved CSF (serum/blood optional) with consent to use it for future research ≥ 3 and ≤ 10 years of follow-up from LP At time of LP untreated and not treated with steroid or off steroids ≥ one month Available/willing to come for in-person follow-up Available/willing to sign the NIH 09-I-0032 Sample processing only consent form Diagnosis of MS based on 2017 McDonald criteria at time of follow-up visit Non-MS Patients selection criteria Required: 25 Non-Inflammatory Neurological Disease (NIND), 25 Other Inflammatory Neurological Disease (OIND) Lumbar puncture (LP) in the untreated stage with cryopreserved CSF (serum/blood optional) with consent to use it for future research ≥ 3 and ≤ 10 years of follow-up from LP At time of LP untreated and not treated with steroid or off steroids ≥ one month Up to date contact information Available/willing to sign the NIH 09-I-0032 Sample processing only consent form Diagnosis: NIND: e.g., ischemic-gliotic changes, CADASIL and other leukodystrophies, migraines, ischemic spinal cord lesions etc OIND: e.g. CNS Sjogren's, SLE, vasculitis, CNS infections, MOG-associated disorders, NMO spectrum disorders (NMOSD)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: For the MS diagnostic test, the investigators will select 50 patients with definite MS (CIS/RIS excluded) and 50 controls, including 25 non-inflammatory neurological diseases (NIND) that mimic MS (such as patients with vascular-ischemic changes, complex migraines, leukodystrophies, etc.) and 25 other inflammatory neurological diseases (OIND) such as NMO, Susac's syndrome, sarcoidosis, CNS vasculitis. For validating the RRMS versus progressive MS classifier, the investigators will select CSF from 50 RRMS and 50 progressive MS patients (25 SPMS and 25 PPMS). Cryopreserved CSF samples from these patients will be analyzed blindly using SOMAscan assay. Probability of MS diagnosis and progressive MS diagnosis will be calculated based on published models. Results will then be unblinded and analyzed for accuracy of diagnostic conclusion. To evaluate the MS severity score, the investigators will select 50 RRMS and 50 progressive MS (25 PPMS and 25 SPMS).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Relapsing Remitting Multiple Sclerosis<br>Blood sample collection Vital signs, weight, height and BMI. Complete neurological examination documented in NeurEx (recorded with an iPAD). Clinical data questionnaire 25FW & non-dominant hand 9HPT (required for calculating CombiWISE & MS-DSS). Smartphone Apps (include 25FW, SDMT and tests that correlate highly w 9HPT - can be acquired in patient-autonomous manner with minimal assistance). Optical Coherence Tomography (OCT) CSF Analysis | Device: SOMAscan<br>* Analysis of previously donated cerebrospinal fluid using a SOMAscan assay<br>|
| Experimental: Progressive Multiple Sclerosis<br>Blood sample collection Vital signs, weight, height and BMI. Complete neurological examination documented in NeurEx (recorded with an iPAD). Clinical data questionnaire 25FW & non-dominant hand 9HPT (required for calculating CombiWISE & MS-DSS). Smartphone Apps (include 25FW, SDMT and tests that correlate highly w 9HPT - can be acquired in patient-autonomous manner with minimal assistance). Optical Coherence Tomography (OCT) CSF Analysis | Device: SOMAscan<br>* Analysis of previously donated cerebrospinal fluid using a SOMAscan assay<br>|
| Experimental: Non-Inflammatory Neurological Diseases<br>Clinical data questionnaire CSF Analysis | Device: SOMAscan<br>* Analysis of previously donated cerebrospinal fluid using a SOMAscan assay<br>|
| Experimental: Other Non-Inflammatory Neurological Diseases<br>Clinical data questionnaire CSF Analysis | Device: SOMAscan<br>* Analysis of previously donated cerebrospinal fluid using a SOMAscan assay<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarker Predicted Outcomes against NeurEx-based outcomes | CSF-biomarker-predicted outcomes against measured NeurEx-based outcomes, considering a Bonferroni-adjusted significance level 0.05/3 = 0.017 (to adjust for 3 tests). | 3 years | 
| MS Severity Model Analyses | As secondary analyses of MS severity model,assessment of correlations between CSF-biomarker-predicted outcomes and more traditional MS outcomes. Specifically, correlate CSF-biomarker-based scores of MS severity and MSSS, ARMSSS and by MS-DSS, calculated from the follow-up visit scores. Based on power calculations, 100 relevant patients/classifier will provide > 90% power to externally validate all 3 Somascan CSF-biomarker-based models. | 3 years |