Analytical validation of a multi‐protein, serum‐based assay for disease activity assessments in multiple sclerosis

Abstract

Purpose To characterize and analytically validate the MSDA Test, a multi‐protein, serum‐based biomarker assay developed using Olink® PEA methodology. Experimental design Two lots of the MSDA Test panel were manufactured and subjected to a comprehensive analytical characterization and validation protocol to detect biomarkers present in the serum of patients with multiple sclerosis (MS). Biomarker concentrations were incorporated into a final algorithm used for calculating four Disease Pathway scores (Immunomodulation, Neuroinflammation, Myelin Biology, and Neuroaxonal Integrity) and an overall Disease Activity score. Results Analytical characterization demonstrated that the multi‐protein panel satisfied the criteria necessary for a fit‐for‐purpose validation considering the assay's intended clinical use. This panel met acceptability criteria for 18 biomarkers included in the final algorithm out of 21 biomarkers evaluated. VCAN was omitted based on factors outside of analytical validation; COL4A1 and GH were excluded based on imprecision and diurnal variability, respectively. Performance of the four Disease Pathway and overall Disease Activity scores met the established acceptability criteria. Conclusions and clinical relevance Analytical validation of this multi‐protein, serum‐based assay is the first step in establishing its potential utility as a quantitative, minimally invasive, and scalable biomarker panel to enhance the standard of care for patients with MS.

Proteomic signatures of physical, cognitive, and imaging outcomes in multiple sclerosis

“…The significantly lower number of available cognitive measures (only 25% of the pwMS) for the baseline time point presents as another study limitation. Moreover, the initial determination of biomarkers within the assay were based on ability to predict presence of contrast‐enhancing and new/newly enlarging lesions 9 . In comparison with younger more active pwMS from the literature, our population was relatively older and had very limited neuroinflammatory activity.…”

“…The MSDA assay uses Proximity Extension Assay (PEA) methodology and is performed on the Olink™ platform. Twenty‐one proteins that are associated with key biological pathways of MS pathophysiology were selected for inclusion on the panel based on results from discovery analyses investigating relative expression of 1196 proteins in previously characterized MS cohorts 9 . For clarification, we did not utilize the pathway or disease activity scores generated by the MSDA panel in our models.…”

“…7 When compared to MRI measures, blood-derived analyses are less costly, more accessible, and can be bundled together with routine clinical blood work. 8 The multiple sclerosis disease activity (MSDA) is a recently developed and analytically validated 9 panel of 18 biomarkers that represent changes within four main pathophysiological pathways of neuroinflammation, immunomodulation, myelin biology, and neuroaxonal integrity. 9 In the first clinical validation study, the MSDA platform was trained and tested as a predictor for presence of gadolinium-enhancing lesions or new/newly enlarging T2 lesions in a cohort of 614 samples.…”

“…8 The multiple sclerosis disease activity (MSDA) is a recently developed and analytically validated 9 panel of 18 biomarkers that represent changes within four main pathophysiological pathways of neuroinflammation, immunomodulation, myelin biology, and neuroaxonal integrity. 9 In the first clinical validation study, the MSDA platform was trained and tested as a predictor for presence of gadolinium-enhancing lesions or new/newly enlarging T2 lesions in a cohort of 614 samples. 10 The multi-protein scores outperformed the best individual protein (NfL) with area under curve change from 0.726 to 0.781.…”

Proximity extension assay‐based proteomics studies in neurodegenerative disorders and multiple sclerosis

“…Furthermore, Qureshi et al developed and validated a serum‐based protein biomarker panel called the MS Disease Activity (MSDA) test using Olink PEA technology (Qureshi et al, 2023). They tested a total of 21 biomarkers, and 18 of them met the criteria.…”