Abstract
The biological pathways involved in amyotrophic lateral sclerosis (ALS) remain elusive and diagnostic decision-making can be challenging. Gene expression studies are valuable in overcoming such challenges since they can shed light on differentially regulated pathways and may ultimately identify valuable biomarkers. This two-stage transcriptome-wide study, including 397 ALS patients and 645 control subjects, identified 2,943 differentially expressed transcripts predominantly involved in RNA binding and intracellular transport. When batch effects between the two stages were overcome, three different models (support vector machines, nearest shrunken centroids, and LASSO) discriminated ALS patients from control subjects in the validation stage with high accuracy. The models’ accuracy reduced considerably when discriminating ALS from diseases that mimic ALS clinically (N = 75), nor could it predict survival. We here show that whole blood transcriptome profiles are able to reveal biological processes involved in ALS. Also, this study shows that using these profiles to differentiate between ALS and mimic syndromes will be challenging, even when taking batch effects in transcriptome data into account.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons in the brain and spinal cord
Baseline characteristics for the 397 amyotrophic lateral sclerosis (ALS) patients, 645 control subjects and 75 ALS-mimics that passed quality control were virtually identical between the different sets (Table 1)
The spectrum of diagnoses in the ALS-mimics reflected the clinical practice of our tertiary referral center for motor neuron diseases (Table A in S1 File)
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons in the brain and spinal cord. Twin studies estimate the heritability of ALS to be 0.61 This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through ZonMW under the aegis of JPND (SOPHIA, STRENGTH). MAvE is supported by NWO (Veni scheme), the Thierry Latran Foundation, the Dutch ALS Foundation and the Rudolf Magnus Brain Center Talent Fellowship. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript
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