Machine learning predicts treatment response to nusinersen in non-sitter Spinal Muscular Atrophy (SMA).

1.1BackgroundNusinersen has substantially increased survival and improved disease progression in Spinal Muscular Atrophy (SMA) patients. However, treatment response is heterogeneous, with some patients gaining the ability to sit and walk whilst others display less obvious changes. MethodFrom the SMA Reach UK and the Italian Telethon Network, 124 non-sitter SMA patients treated with nusinersen under 4 years were included and randomly allocated to training and testing (80/20%). Tree and regression-based machine learning for survival outcomes were compared, and oblique random forests were selected, with a testing C-Index of 0.74. The features were selected from items of the CHOP-INTEND and HINE-2 motor function assessments, respiratory and swallowing status using mutual information. FindingsSixty-two patients (50%) achieved sitting, at a median age of 2.4 years. The predicted median time-to-sitting in those requiring tube feeding at treatment initiation was 4-months later than those without, and this was the most influential factor. Specific motor function features, including the ability to kick in supine, were strongly associated with a higher likelihood of sitting. InterpretationThis work provides a framework for predicting nusinersen-response and represents the first stage in personalised counselling on treatment plans for SMA. FundingSupport for SMA Reach is provided by Biogen, Roche and Novartis, and historically NIHR BRC, SMA Trust, the MRC Translational Research Centre and MD UK. Support for the Italian network is provided by Famiglie SMA, Telethon (GSP 13002), and ASAMSI. 1.2 Research Into ContextO_ST_ABSEvidence before this studyC_ST_ABSA literature search on PubMed up to January 1st 2025 with the term "("Spinal Muscular Atrophy" OR "SMA") AND ("Nusinersen" OR "Spinraza" OR "ISIS-SMNRx" OR "ISIS 396443") AND ("predict*")" across all fields was performed. Achievement of sitting after nusinersen treatment in SMA 1 has been linked to the age of treatment, symptom onset and general motor function severity (CHOP-INTEND and HINE-2 score), but no multivariable analysis or prediction of outcomes after treatment was found. Added value of this studyOur study identifies key patient features that are linked to nusinersen treatment response in non-sitter SMA 1 patients. This work provides a higher level of granularity beyond previous univariate models, yielding a framework for predicting personalised patient sitting. Crucially, we highlight that bulbar impairment as a proxy for disease severity is very influential in predicting a patients likelihood of sitting, along with specific motor function abilities at baseline. Implications of all the available evidenceDespite considerable evidence of efficacy, this work provides insights into the homogenous gross motor function response observed in SMA patients treated with nusinersen, which has been under researched. The results of this study provide individualised predictions of the likelihood of patients outcomes after treatment with nusinersen. Crucially, this work can inform clinicians in their discussions on treatment-response with parents and carers of babies with SMA.