Plasma isomiRs as Candidate Biomarkers for Amyotrophic Lateral Sclerosis
Rogan G Magee1, Vivianna M Van Deerlin2, Corey T McMillan1,3
1Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Background And Objectives:
There are no FDA-approved diagnostic biomarkers for amyotrophic lateral sclerosis (ALS). TDP-43 is a known cofactor in the cleavage of long premature microRNAs (miRNAs) into their short, mature products. isomiRs are miRNA variants that differ in their 5' and 3' end points and regulate distinct mRNA targets. In this study, we tested the hypotheses that circulating isomiR profiles differ in the context of TAR DNA-binding Protein pathology and that isomiRs are superior to miRNAs for classification of ALS.
Methods:
We obtained RNA from plasma samples of 14 patients with ALS and 14 age-matched and sex-matched controls for sequencing on a NextSeq 2000. Data were processed using Unique Molecular Identifier tools and a custom pipeline designed to match miRNA variant sequences without mismatches. Differential expression (DE) was identified using DEseq2 at FDR ≤ 0.1. XGBoost classifiers were built using a subset of (Model 1) isomiRs or (Model 2) miRNAs that were present above a median threshold in all sequencing batches. Parameters were tuned using grid search and 10-fold cross-validation while training to distinguish ALS samples from controls among a single large public data set. Models were then validated on in-house samples and 1 publicly available holdout data set.
Results:
Fourteen (0.2%), 355 (2.7%), and 14 (0.7%) isomiRs were differentially expressed in in-house plasma, public ALS plasma, and public ALS serum, respectively. One (0.1%), 94 (5.5%), and 13 (2.4%) miRNAs were differentially expressed, respectively. Model 1 accurately classified in-house ALS plasma and public ALS serum (area under the curve [AUC] = 0.87) and did not distinguish 40 of 41 Alzheimer disease samples from control plasma (GSE215789; AUC = 0.47) or 60 of 77 Parkinson disease samples from control whole blood (GSE180193; AUC = 0.55). In comparison, Model 2 using miRNAs performed worse on in-house plasma (AUC = 0.49).
Discussion:
Analyzing individual isomiRs may improve the performance of circulating noncoding RNAs as diagnostic biomarkers of ALS.
Insights
Analyzing isomiR profiles in plasma shows promise for diagnosing amyotrophic lateral sclerosis (ALS). These microRNA variants (isomiRs) offer better classification accuracy than standard microRNAs (miRNAs) for ALS detection.
Area of Science:
- Biochemistry
- Genomics
- Biomarker Discovery
Background:
- Amyotrophic lateral sclerosis (ALS) currently lacks FDA-approved diagnostic biomarkers.
- MicroRNAs (miRNAs) are crucial regulators, and their variants, isomiRs, may offer distinct diagnostic potential.
- TDP-43 protein pathology is linked to miRNA processing, suggesting a role for isomiRs in ALS.
Purpose of the Study:
- To investigate if circulating isomiR profiles differ in patients with ALS.
- To determine if isomiRs are superior to miRNAs for classifying ALS.
- To explore the diagnostic utility of isomiRs as biomarkers for ALS.
Main Methods:
- Plasma RNA from 14 ALS patients and 14 controls was sequenced.
- A custom pipeline processed sequencing data to identify isomiRs and miRNAs.
- XGBoost classifiers were trained using isomiRs (Model 1) and miRNAs (Model 2) for ALS classification.
Main Results:
- Significantly more isomiRs than miRNAs were differentially expressed between ALS and control samples.
- Model 1 (isomiRs) achieved an AUC of 0.87 for classifying ALS in plasma and serum.
- Model 2 (miRNAs) performed poorly (AUC = 0.49) in classifying ALS in plasma.
Conclusions:
- Individual isomiRs show potential as superior biomarkers for ALS diagnosis.
- Circulating isomiR analysis may enhance the performance of noncoding RNAs for ALS biomarker discovery.
- Further research into isomiRs could lead to improved diagnostic tools for ALS.
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