CausalDiffChem: Causal Network Restoration for Therapeutic Prioritization and Repurposing Across Diseases
Armah F, Abor E, Sam P, Sarpong E, Ghartey-Kwansah G.. Research Square, 2026-10-26
Topic: Genetics and APOE
Computational drug repurposing commonly relies on transcriptomic signature matching to identify compounds that reverse disease-associated gene expression, but such approaches do not distinguish putative causal drivers from downstream consequences of disease. Here, we present CausalDiffChem, a causal-network-guided framework that reconstructs disease-specific structural causal models from transcriptomic data using the NOTEARS algorithm and prioritizes compounds according to net_correction, a measure of network restoration under a simulated intervention propagated through the inferred linear structural causal model. We applied CausalDiffChem to multiple sclerosis, sarcoidosis, leishmaniasis and Alzheimer's disease, comprising 408 disease samples and 374 healthy controls. Independently reconstructed networks recovered biologically coherent disease-associated architecture, including a dominant apolipoprotein D interaction in Alzheimer's disease and a macrophage-associated regulatory axis in sarcoidosis. Screening FDA-approved, clinical-stage and preclinical compound libraries identified disease-specific candidates and recurrent prioritization across independently constructed networks. Cisplatin ranked first in both the FDA-approved and clinical-stage sarcoidosis libraries and recurred among the top-ranked candidates across multiple diseases, whereas memantine hydrochloride ranked first across all three compound libraries in leishmaniasis with identical restoration scores. Gene-level analyses further showed that high aggregate restoration could coexist with limited correction of dominant network interactions or discordant global alignment, demonstrating that network restoration, breadth and global transcriptional similarity capture complementary dimensions of therapeutic response. CausalDiffChem therefore provides an interpretable framework for prioritizing therapeutics according to their predicted effects on disease-specific regulatory structure, without requiring curated pathway annotations, and generates experimentally testable hypotheses for drug repurposing across heterogeneous diseases.
Key findings
- Gene-level analyses further showed that high aggregate restoration could coexist with limited correction of dominant network interactions or discordant global alignment, demonstrating that network restoration, breadth and global transcriptional similarity capture complementary dimensions of therapeutic response.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Armah, F., Abor, E., Sam, P., Sarpong, E., & Ghartey-Kwansah, G. (2026). CausalDiffChem: Causal Network Restoration for Therapeutic Prioritization and Repurposing Across Diseases. Research Square. https://doi.org/10.21203/rs.3.rs-11272130/v1
Vancouver
Armah F, Abor E, Sam P, Sarpong E, Ghartey-Kwansah G. CausalDiffChem: Causal Network Restoration for Therapeutic Prioritization and Repurposing Across Diseases. Research Square. 2026. doi:10.21203/rs.3.rs-11272130/v1.
BibTeX
@article{armah2026-0dd7e989,
author = {Armah, F. and Abor, E. and Sam, P. and Sarpong, E. and Ghartey-Kwansah, G.},
title = {{CausalDiffChem: Causal Network Restoration for Therapeutic Prioritization and Repurposing Across Diseases}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11272130/v1},
url = {https://doi.org/10.21203/rs.3.rs-11272130/v1}
}
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