SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy

Biomarkers for Spinal Muscular Atrophy Study Group; Pediatric Neuromuscular Clinical Research Network

doi:10.1371/journal.pone.0060113

SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy

Biomarkers for Spinal Muscular Atrophy Study Group, Pediatric Neuromuscular Clinical Research Network

Research output: Contribution to journal › Article › peer-review

42 Scopus citations

Abstract

Objectives: Spinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS). Methods: BforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores. Results: 12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13^th analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures. Conclusions: Discovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.

Original language	English (US)
Article number	e60113
Journal	PloS one
Volume	8
Issue number	4
DOIs	https://doi.org/10.1371/journal.pone.0060113
State	Published - Apr 2 2013

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences
General

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10.1371/journal.pone.0060113

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@article{610952eafc4040b4a0719d1f0230b2b1,

title = "SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy",

abstract = "Objectives: Spinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS). Methods: BforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores. Results: 12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13th analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures. Conclusions: Discovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.",

author = "{Biomarkers for Spinal Muscular Atrophy Study Group} and {Pediatric Neuromuscular Clinical Research Network} and Kobayashi, {Dione T.} and Jing Shi and Laurie Stephen and Ballard, {Karri L.} and Ruth Dewey and James Mapes and Brett Chung and Kathleen McCarthy and Swoboda, {Kathryn J.} and Crawford, {Thomas O.} and Rebecca Li and Thomas Plasterer and Cynthia Joyce and G. Acsadi and C. Campbell and A. Coates and Connolly, {A. M.} and Iannaccone, {S. T.} and C. Khongkhatithum and Kissel, {J. T.} and Kolb, {S. J.} and Kunz, {N. L.} and C. Makris and Mathews, {K. D.} and D. Matthews and Schroth, {M. K.} and J. Vajsar and Wang, {C. H.} and Wong, {B. L.} and M. Sahin and L. Antiel and J. Florence and R. Gee and Glanzman, {A. M.} and J. Hartman and W. King and K. Krosschell and K. Laubenthal and M. McGuire and J. Montes and L. Nelson and J. Owen and K. Patterson and J. Quigley and C. Roman and S. Riley and C. Scholtes and P. Sedlacek and C. Siener and S. Strumpf",

year = "2013",

month = apr,

day = "2",

doi = "10.1371/journal.pone.0060113",

language = "English (US)",

volume = "8",

journal = "PloS one",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "4",

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TY - JOUR

T1 - SMA-MAP

T2 - A Plasma Protein Panel for Spinal Muscular Atrophy

AU - Biomarkers for Spinal Muscular Atrophy Study Group

AU - Pediatric Neuromuscular Clinical Research Network

AU - Kobayashi, Dione T.

AU - Shi, Jing

AU - Stephen, Laurie

AU - Ballard, Karri L.

AU - Dewey, Ruth

AU - Mapes, James

AU - Chung, Brett

AU - McCarthy, Kathleen

AU - Swoboda, Kathryn J.

AU - Crawford, Thomas O.

AU - Li, Rebecca

AU - Plasterer, Thomas

AU - Joyce, Cynthia

AU - Acsadi, G.

AU - Campbell, C.

AU - Coates, A.

AU - Connolly, A. M.

AU - Iannaccone, S. T.

AU - Khongkhatithum, C.

AU - Kissel, J. T.

AU - Kolb, S. J.

AU - Kunz, N. L.

AU - Makris, C.

AU - Mathews, K. D.

AU - Matthews, D.

AU - Schroth, M. K.

AU - Vajsar, J.

AU - Wang, C. H.

AU - Wong, B. L.

AU - Sahin, M.

AU - Antiel, L.

AU - Florence, J.

AU - Gee, R.

AU - Glanzman, A. M.

AU - Hartman, J.

AU - King, W.

AU - Krosschell, K.

AU - Laubenthal, K.

AU - McGuire, M.

AU - Montes, J.

AU - Nelson, L.

AU - Owen, J.

AU - Patterson, K.

AU - Quigley, J.

AU - Roman, C.

AU - Riley, S.

AU - Scholtes, C.

AU - Sedlacek, P.

AU - Siener, C.

AU - Strumpf, S.

PY - 2013/4/2

Y1 - 2013/4/2

N2 - Objectives: Spinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS). Methods: BforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores. Results: 12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13th analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures. Conclusions: Discovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.

AB - Objectives: Spinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS). Methods: BforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores. Results: 12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13th analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures. Conclusions: Discovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.

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U2 - 10.1371/journal.pone.0060113

DO - 10.1371/journal.pone.0060113

M3 - Article

C2 - 23565191

SN - 1932-6203

VL - 8

JO - PloS one

JF - PloS one

IS - 4

M1 - e60113

ER -

SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy

Abstract

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