Machine learning algorithms to classify spinal muscular atrophy subtypes

Srivastava, T.; Darras, Basil T.; Wu, Jim S.; Rutkove, Seward B.

doi:10.1212/wnl.0b013e3182604395

Cited by 23 publications

(22 citation statements)

References 31 publications

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“…We have recently demonstrated such an approach in spinal muscular atrophy. 20 The application of such a strategy in DMD may ultimately assist in speeding clinical therapeutic trials.…”

Section: Discussionmentioning

confidence: 99%

Cross-sectional Evaluation of Electrical Impedance Myography and Quantitative Ultrasound for the Assessment of Duchenne Muscular Dystrophy in a Clinical Trial Setting

Rutkove¹,

Geisbush²,

Mijailovic³

et al. 2014

Pediatric Neurology

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BACKGROUND Electrical impedance myography (EIM) and quantitative ultrasound (QUS) are two non-invasive, painless, and effort-independent approaches for assessing neuromuscular disease. Both techniques have potential to serve as useful biomarkers in clinical trials in Duchenne muscular dystrophy (DMD). However, their comparative sensitivity to disease status and how they relate to one another is unknown. METHODS We performed a cross-sectional analysis of EIM and QUS in 24 healthy boys and 24 with DMD, aged 2-14 years with trained research assistants performing all measurements. Three upper and three lower extremity muscles were studied unilaterally in each child and the data averaged for each individual. RESULTS Both EIM and QUS differentiated healthy boys from those with DMD (p<0.001 for both). QUS values correlated with age in DMD boys (rho=0.45, p=0.029), whereas EIM did not (rho=−0.31, p=0.14). However, EIM phase correlated with age in healthy boys (rho=0.51, p= 0.012) whereas QUS did not (rho =−0.021, p =0.92). In DMD boys, EIM phase correlated with the North Star Ambulatory Assessment (EIM: rho=0.65, p=0.022); QUS showed a near-significant association (rho=−0.56, p=0.060). The two technologies trended toward a moderate correlation with one another in the DMD cohort but not in the healthy group (rho=−0.40, p=0.054, rho=−0.32, p=0.13, respectively). CONCLUSIONS EIM and QUS are complementary modalities for the assessment of boys with DMD; further study and application of these two modalities alone or in combination in a longitudinal fashion is warranted.

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“…We have recently demonstrated such an approach in spinal muscular atrophy. 20 The application of such a strategy in DMD may ultimately assist in speeding clinical therapeutic trials.…”

Section: Discussionmentioning

confidence: 99%

Cross-sectional Evaluation of Electrical Impedance Myography and Quantitative Ultrasound for the Assessment of Duchenne Muscular Dystrophy in a Clinical Trial Setting

Rutkove¹,

Geisbush²,

Mijailovic³

et al. 2014

Pediatric Neurology

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“…The motor prediction tool itself could be expanded with additional modeling and also data from future analyses. Work is ongoing to build an accessory tool to classify SMA into types akin to Srivivasta et al by using machine learning and other models [76]. Such a tool could be used in trials or clinical practice to track a patient’s ‘type’ over time to assess whether they are transitioning towards a more severe or mild phenotype.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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ObjectivesSpinal 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).MethodsBforSMA 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.Results12 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.ConclusionsDiscovery 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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“…EIM is a more recently developed biomarker that has shown promise in SMA (Rutkove, 2009; Rutkove et al, 2012b; Rutkove et al, 2010; Srivastava et al, 2012). As with other electrical bioimpedance-based applications, e.g.…”

Section: Introductionmentioning

confidence: 99%

The neuromuscular impact of symptomatic SMN restoration in a mouse model of spinal muscular atrophy

Arnold

McGovern

Sanchez

et al. 2016

Neurobiology of Disease

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Background Significant advances in the development of SMN-restoring therapeutics have occurred since 2010 when very effective biological treatments were reported in mouse models of spinal muscular atrophy. As these treatments are applied in human clinical trials, there is pressing need to define quantitative assessments of disease progression, treatment stratification, and therapeutic efficacy. The electrophysiological measures Compound Muscle Action Potential and Motor Unit Number Estimation are reliable measures of nerve function. In both the SMNΔ7 mouse and a pig model of spinal muscular atrophy, early SMN restoration results in preservation of electrophysiological measures. Currently, clinical trials are underway in patients at post-symptomatic stages of disease progression. In this study, we present results from both early and delayed SMN restoration using clinically-relevant measures including electrical impedance myography, compound muscle action potential, and motor unit number estimation to quantify the efficacy and time-sensitivity of SMN-restoring therapy. Methods SMAΔ7 mice were treated via intracerebroventricular injection with antisense oligonucleotides targeting ISS-N1 to increase SMN protein from the SMN2 gene on postnatal day 2, 4, or 6 and compared with sham-treated spinal muscular atrophy and control mice. Compound muscle action potential and motor unit number estimation of the triceps surae muscles were performed at day 12, 21, and 30 by a single evaluator blinded to genotype and treatment. Similarly, electrical impedance myography was measured on the biceps femoris muscle at 12 days for comparison. Results Electrophysiological measures and electrical impedance myography detected significant differences at 12 days between control and late-treated (4 or 6 days) and sham-treated spinal muscular atrophy mice, but not in mice treated at 2 days(p<0.01). EIM findings paralleled and correlated with compound muscle action potential and motor unit number estimation (r=0.61 and r=0.50, respectively, p<0.01). Longitudinal measures at 21 and 30 days show that symptomatic therapy results in reduced motor unit number estimation associated with delayed normalization of compound muscle action potential. Conclusions The incomplete effect of symptomatic treatment is accurately identified by both electrophysiological measures and electrical impedance myography. There is strong correlation between these measures and with weight and righting reflex. This study predicts that measures of compound muscle action potential, motor unit number estimation, and electrical impedance myography are promising biomarkers of treatment stratification and effect for future spinal muscular atrophy trials. The ease of application and simplicity of electrical impedance myography compared with standard electrophysiological measures may be particularly valuable in future pediatric clinical trials.

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Machine learning algorithms to classify spinal muscular atrophy subtypes

Cited by 23 publications

References 31 publications

Cross-sectional Evaluation of Electrical Impedance Myography and Quantitative Ultrasound for the Assessment of Duchenne Muscular Dystrophy in a Clinical Trial Setting

Cross-sectional Evaluation of Electrical Impedance Myography and Quantitative Ultrasound for the Assessment of Duchenne Muscular Dystrophy in a Clinical Trial Setting

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

The neuromuscular impact of symptomatic SMN restoration in a mouse model of spinal muscular atrophy

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