Dataset Information

RNA sequencing of peripheral blood in amyotrophic lateral sclerosis reveals distinct molecular subtypes: Considerations for biomarker discovery.

ABSTRACT:

Aim

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease with limited therapeutic options. A key factor limiting the development of effective therapeutics is the lack of disease biomarkers. We sought to assess whether biomarkers for diagnosis, prognosis or cohort stratification could be identified by RNA sequencing (RNA-seq) of ALS patient peripheral blood.

Methods

Whole blood RNA-seq data were generated for 96 Australian sporadic ALS (sALS) cases and 48 healthy controls (NCBI GEO accession GSE234297). Differences in sALS-control gene expression, transcript usage and predicted leukocyte proportions were assessed, with pathway analysis used to predict the activity state of biological processes. Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning algorithms were applied to search for diagnostic and prognostic gene expression patterns. Unsupervised clustering analysis was employed to determine whether sALS patient subgroups could be detected.

Results

Two hundred and forty-five differentially expressed genes were identified in sALS patients relative to controls, with enrichment of immune, metabolic and stress-related pathways. sALS patients also demonstrated switches in transcript usage across a small set of genes. We established a classification model that distinguished sALS patients from controls with an accuracy of 78% (sensitivity: 79%, specificity: 75%) using the expression of 20 genes. Clustering analysis identified four patient subgroups with gene expression signatures and immune cell proportions reflective of distinct peripheral effects.

Conclusions

Our findings suggest that peripheral blood RNA-seq can identify diagnostic biomarkers and distinguish molecular subtypes of sALS patients however, its prognostic value requires further investigation.

SUBMITTER: Grima N

PROVIDER: S-EPMC10946588 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Publications

RNA sequencing of peripheral blood in amyotrophic lateral sclerosis reveals distinct molecular subtypes: Considerations for biomarker discovery.

Grima Natalie N Liu Sidong S Southwood Dean D Henden Lyndal L Smith Andrew A Lee Albert A Rowe Dominic B DB D'Silva Susan S Blair Ian P IP Williams Kelly L KL

Neuropathology and applied neurobiology 20231201 6

<h4>Aim</h4>Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease with limited therapeutic options. A key factor limiting the development of effective therapeutics is the lack of disease biomarkers. We sought to assess whether biomarkers for diagnosis, prognosis or cohort stratification could be identified by RNA sequencing (RNA-seq) of ALS patient peripheral blood.<h4>Methods</h4>Whole blood RNA-seq data were generated for 96 Australian sporadic ALS (sALS) cases and 4 ...[more]

PMID: 37818590

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Project description:Thoughtful clinical trial design is critical for efficient therapeutic development, particularly in the field of amyotrophic lateral sclerosis (ALS), where trials often aim to detect modest treatment effects among a population with heterogeneous disease progression. Appropriate outcome measure selection is necessary for trials to provide decisive and informative results. Investigators must consider the outcome measure's reliability, responsiveness to detect change when change has actually occurred, clinical relevance, and psychometric performance. ALS clinical trials can also be performed more efficiently by utilizing statistical enrichment techniques. Innovations in ALS prediction models allow for selection of participants with less heterogeneity in disease progression rates without requiring a lead-in period, or participants can be stratified according to predicted progression. Statistical enrichment can reduce the needed sample size and improve study power, but investigators must find a balance between optimizing statistical efficiency and retaining generalizability of study findings to the broader ALS population. Additional progress is still needed for biomarker development and validation to confirm target engagement in ALS treatment trials. Selection of an appropriate biofluid biomarker depends on the treatment mechanism of interest, and biomarker studies should be incorporated into early phase trials. Inclusion of patients with ALS as advisors and advocates can strengthen clinical trial design and study retention, but more engagement efforts are needed to improve diversity and equity in ALS research studies. Another challenge for ALS therapeutic development is identifying ways to respect patient autonomy and improve access to experimental treatment, something that is strongly desired by many patients with ALS and ALS advocacy organizations. Expanded access programs that run concurrently to well-designed and adequately powered randomized controlled trials may provide an opportunity to broaden access to promising therapeutics without compromising scientific integrity or rushing regulatory approval of therapies without adequate proof of efficacy.

Dataset Information

RNA sequencing of peripheral blood in amyotrophic lateral sclerosis reveals distinct molecular subtypes: Considerations for biomarker discovery.

Aim

Methods

Results

Conclusions

Publications

RNA sequencing of peripheral blood in amyotrophic lateral sclerosis reveals distinct molecular subtypes: Considerations for biomarker discovery.

Similar Datasets

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