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Top novel candidate Hypothesis #2091 high quality

Ketogenic diet → Sod1 → ALS

Cross-domain hypothesis: Epilepsy drug → ALS outcome

Figure 1. Hypothesis chain: Ketogenic diet (upregulates) Sod1 (associated with) ALS.
Established repurposing
Outreach score
0.383
Evidence A → B
1
papers
Evidence B → C
22
papers
Direct A → C
0
papers

Evidence network

The full set of scientific papers supporting this hypothesis, visualized as a force-directed graph. Each gray node is one paper; hover for the extracted claim, click to open it on PubMed.

Figure 2. Evidence network for Ketogenic diet → Sod1 → ALS. Each gray node represents a scientific paper from the Robertium extraction. A→B edges show Ketogenic diet → Sod1 claims; B→C edges show Sod1 → ALS claims. Hover for details, click a paper to open PubMed.
View as text list

A→B papers (1)

  • PMID 31873138 — Ketogenic diet induces skeletal muscle atrophy via reducing muscle protein synthesis and possibly activating proteolysis in mice (2019) · in all examined muscles of mice conf 0.90

B→C papers (22)

  • PMID 41513843 — Demographic, clinical and genetic characteristics of patients with amyotrophic lateral sclerosis from two specialised centres in Austria (2026) · in Austrian ALS patients conf 0.80
  • PMID 41852184 — High Prevalence of <scp> <i>SOD1</i> </scp> Pathogenic Variants in the <scp>UK</scp> Biobank: Implications for Early Intervention in Amyotrophic Lateral Sclerosis (2026) · in European patients conf 0.90
  • PMID 40957416 — Landscapes of missense variant impact for human superoxide dismutase 1 (2025) · Amyotrophic lateral sclerosis (ALS) conf 0.90
  • PMID 40050936 — Impact of cysteine mutations on the structural dynamics and functional impairment of SOD1: insights into the pathogenicity of amyotrophic lateral sclerosis (2025) · mutations in SOD1 conf 0.80
  • PMID 40763713 — Epidemiology of Amyotrophic Lateral Sclerosis in Western and Northern Finland (2025) · in Finnish ALS patients conf 0.70
  • PMID 41276866 — Cutting-edge treatments in amyotrophic lateral sclerosis: the role of molecular pathogenesis in targeted therapies (2025) · familial and sporadic forms conf 0.90
  • PMID 41283823 — Amyotrophic lateral sclerosis in Saudi Arabia: a multicenter descriptive study (2025) · in Saudi Arabian ALS patients conf 0.80
  • PMID 41359166 — Four families with slowly progressive ALS due to p.Val120Leu SOD1 variant in Northeast Brazil (2025) · in four families with p.Val120Leu variant from Northeast Brazil, slowly progressive with incomplete penetrance conf 0.95
  • PMID 37159497 — Advantages of routine next‐generation sequencing over standard genetic testing in the amyotrophic lateral sclerosis clinic (2023) · in ALS patients conf 0.85
  • PMID 34996976 — SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity (2022) · amyotrophic lateral sclerosis patients conf 0.95
  • PMID 36549973 — Genetic landscape of ALS in Malta based on a quinquennial analysis (2022) · in Maltese ALS patients conf 0.90
  • PMID 34518333 — De novo mutations in <i>SOD1</i> are a cause of ALS (2021) · in ALS patients from Germany, South Korea, and Sweden conf 0.90
  • PMID 33630959 — Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis (2021) · in literature and databases conf 0.95
  • PMID 33414559 — Genetic analysis of ALS cases in the isolated island population of Malta (2021) · in Maltese ALS patient cohort conf 0.90
  • PMID 33208543 — Mutational Analysis of Known ALS Genes in an Italian Population-Based Cohort (2020) · Italian population-based cohort conf 0.80
  • PMID 32739880 — Generation of an induced pluripotent stem cell line, CSSi011-A (6534), from an Amyotrophic lateral sclerosis patient with heterozygous L145F mutation in SOD1 gene (2020) · familial conf 0.90
  • PMID 31747286 — An Allosteric Pathway in Copper, Zinc Superoxide Dismutase Unravels the Molecular Mechanism of the G93A Amyotrophic Lateral Sclerosis-Linked Mutation (2019) · several different mutations conf 0.95
  • PMID 29493298 — Phenotypic and genotypic studies of ALS cases in ALS-SMA families (2018) · in ALS-SMA families conf 0.80
  • PMID 29149916 — Whole-exome sequencing in amyotrophic lateral sclerosis suggests NEK1 is a risk gene in Chinese (2017) · Chinese population conf 0.90
  • PMID 28291249 — Analysis of SOD1 mutations in a Chinese population with amyotrophic lateral sclerosis: a case-control study and literature review (2017) · in Chinese populations conf 0.90
  • PMID 27978769 — Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center (2016) · in Brazilian FALS patients conf 0.80
  • PMID 30512582 — [Epidemiology of amyotrophic lateral sclerosis]. (2016) · familial ALS conf 0.90

Clinical trials

3 registered trials for Ketogenic diet in ALS

Source: ClinicalTrials.gov

Provenance trace

Full audit trail of how this hypothesis was generated: source papers, extracted claims, bridging logic, embedding model, and scoring. Every step is recorded and reproducible.

Provenance trace

Audit trail · Ketogenic diet → Sod1 → ALS

23 source papers, 23 extracted claims, scored by Swanson ABC chain.

Backfilled

Backfilled retroactively from DB state on 2026-05-13. The pipeline_run this row references was created by the backfill script, not by the actual generation orchestrator. Source papers, claims, scoring, and embedding config are recovered; generation-time metadata (exact git commit at gen time, host, exact command) is not recoverable.

1Source papers23
Filter
2Extracted claims23

Each row is one structured triple extracted by deepseek-v4-flash (prompt v1_2026_05_07, source: configured). Confidence is the LLM's self-rating.

  • Ketogenic dietupregulatesSod1A→B
    "in all examined muscles of mice"confidence 0.90· extraction run #14· claim #17656
  • SOD1associated_withALSB→C
    "amyotrophic lateral sclerosis patients"confidence 0.95· extraction run #15· claim #27747
  • SOD1causesALSB→C
    "several different mutations"confidence 0.95· extraction run #15· claim #28935
  • SOD1causesALSB→C
    "in ALS patients from Germany, South Korea, and Sweden"confidence 0.90· extraction run #15· claim #29387
  • SOD1associated_withALSB→C
    "in literature and databases"confidence 0.95· extraction run #15· claim #31154
  • SOD1causesALSB→C
    "Italian population-based cohort"confidence 0.80· extraction run #15· claim #31514
  • SOD1associated_withALSB→C
    "Chinese population"confidence 0.90· extraction run #15· claim #31935
  • SOD1associated_withALSB→C
    "in Maltese ALS patient cohort"polarity: negativeconfidence 0.90· extraction run #15· claim #32056
  • SOD1causesALSB→C
    "in ALS patients"confidence 0.85· extraction run #15· claim #34183
  • SOD1causesALSB→C
    "Amyotrophic lateral sclerosis (ALS)"confidence 0.90· extraction run #15· claim #34299
  • SOD1causesALSB→C
    "in Chinese populations"confidence 0.90· extraction run #15· claim #34718
  • SOD1associated_withALSB→C
    "in Maltese ALS patients"polarity: negativeconfidence 0.90· extraction run #15· claim #35925
  • SOD1associated_withALSB→C
    "in Brazilian FALS patients"confidence 0.80· extraction run #21· claim #98134
  • SOD1associated_withALSB→C
    "in ALS-SMA families"confidence 0.80· extraction run #21· claim #98898
  • SOD1associated_withALSB→C
    "mutations in SOD1"confidence 0.80· extraction run #21· claim #99245
  • SOD1causesALSB→C
    "familial"confidence 0.90· extraction run #21· claim #100263
  • SOD1causesALSB→C
    "familial ALS"confidence 0.90· extraction run #21· claim #100508
  • SOD1associated_withALSB→C
    "in Finnish ALS patients"confidence 0.70· extraction run #21· claim #102162
  • SOD1associated_withALSB→C
    "familial and sporadic forms"confidence 0.90· extraction run #21· claim #102514
  • SOD1associated_withALSB→C
    "in Saudi Arabian ALS patients"confidence 0.80· extraction run #21· claim #102500
  • SOD1causesALSB→C
    "in four families with p.Val120Leu variant from Northeast Brazil, slowly progressive with incomplete penetrance"confidence 0.95· extraction run #21· claim #102582
  • SOD1associated_withALSB→C
    "in Austrian ALS patients"confidence 0.80· extraction run #21· claim #102832
  • SOD1associated_withALSB→C
    "in European patients"confidence 0.90· extraction run #21· claim #103428
3Bridging logicSwanson ABC
Drug
Ketogenic diet
upregulates
→
1 paper
Mediator
Sod1
associated_with
→
22 papers
Outcome
ALS
edge_support_log_ab
log(ab + 1) = 0.693
edge_support_log_bc
log(bc + 1) = 3.135
novelty_factor
1.000 (no direct drug→outcome evidence — full novelty)
direct_a_to_c_count
0
4Embedding modelbge-m3

Embeddings are used at the L1 filtering stage to prune off-topic abstracts before claim extraction. They do not directly score the hypothesis.

model
bge-m3
dim
1024
max_length
8192 tokens
similarity_scores
No per-hypothesis cosine scores stored.
5Final scoringhigh · 0.383
method
swanson_abc_log_evidence_with_novelty_penalty
formula
score = min((log(ab+1) + log(bc+1)) * novelty / 10, 1.0); novelty = 1.0 if direct==0 else 0.7 / (direct+1)
raw score
0.3829
outreach score
0.3829
quality tier
high
Pipeline version
9996ffa
Pipeline run
id 4 · uuid eb8b7730…
Pipeline command
scripts/backfill_provenance_v2.py:v2_2026_05_12
Pipeline status
completed
Generated
2026-05-12 21:43:39 UTC
Schema version
1.0
Download full provenance JSON

Horizontal exploration

Similar hypotheses

Closest 8 of 1,618 hypotheses, ranked by hybrid score (50% bge-m3 embedding cosine · 40% drug/mediator/outcome overlap · 10% shared evidence papers).

  1. Alternative drug0.87
    sodium butyrate→Sod1→ALS

    Different drug, same disease outcome

    ALShigh
  2. Alternative drug0.87
    LWE→SOD1→ALS

    Different drug, same disease outcome

    ALShigh
  3. Alternative drug0.87
    saxagliptin→SOD1→ALS

    Different drug, same disease outcome

    ALShigh
  4. New indication0.81
    Ketogenic diet→Sod1→familial ALS

    Same drug + same mediator, different disease

    ALSmid
  5. New indication0.81
    Ketogenic diet→Sod1→familial amyotrophic lateral sclerosis

    Same drug + same mediator, different disease

    ALSmid
Show 3 more
  1. Cross-indication0.78
    Ketogenic diet→GFAP→cognitive decline

    Same drug, different disease — potential alternate indication

    Alzheimermid
  2. Cross-indication0.77
    Ketogenic diet→GFAP→cognitive impairment

    Same drug, different disease — potential alternate indication

    Alzheimermid
  3. Alternative drug0.73
    TOL→SOD1→ALS

    Different drug, same disease outcome

    ALSmid

The drug — Ketogenic diet

Source domain: Epilepsy · entity type: drug

View all hypotheses for Ketogenic diet →

The mediator — Sod1

Entity type: gene

The outcome — ALS

Target domain: ALS · entity type: disease

Evidence

Limited evidence base in our current extraction. Treat this hypothesis as a starting point for further literature review, not a settled conclusion.

A → B evidence: Ketogenic diet upregulates Sod1

  • PMID 31873138 Ketogenic diet induces skeletal muscle atrophy via reducing muscle protein synthesis and possibly activating proteolysis in mice (2019)

B → C evidence: Sod1 associated with ALS

  • PMID 41513843 Demographic, clinical and genetic characteristics of patients with amyotrophic lateral sclerosis from two specialised centres in Austria (2026)
  • PMID 41852184 High Prevalence of <scp> <i>SOD1</i> </scp> Pathogenic Variants in the <scp>UK</scp> Biobank: Implications for Early Intervention in Amyotrophic Lateral Sclerosis (2026)
  • PMID 40957416 Landscapes of missense variant impact for human superoxide dismutase 1 (2025)
  • PMID 40050936 Impact of cysteine mutations on the structural dynamics and functional impairment of SOD1: insights into the pathogenicity of amyotrophic lateral sclerosis (2025)
  • PMID 40763713 Epidemiology of Amyotrophic Lateral Sclerosis in Western and Northern Finland (2025)
  • PMID 41276866 Cutting-edge treatments in amyotrophic lateral sclerosis: the role of molecular pathogenesis in targeted therapies (2025)
  • PMID 41283823 Amyotrophic lateral sclerosis in Saudi Arabia: a multicenter descriptive study (2025)
  • PMID 41359166 Four families with slowly progressive ALS due to p.Val120Leu SOD1 variant in Northeast Brazil (2025)
  • PMID 37159497 Advantages of routine next‐generation sequencing over standard genetic testing in the amyotrophic lateral sclerosis clinic (2023)
  • PMID 34996976 SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity (2022)
  • PMID 36549973 Genetic landscape of ALS in Malta based on a quinquennial analysis (2022)
  • PMID 34518333 De novo mutations in <i>SOD1</i> are a cause of ALS (2021)
  • PMID 33630959 Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis (2021)
  • PMID 33414559 Genetic analysis of ALS cases in the isolated island population of Malta (2021)
  • PMID 33208543 Mutational Analysis of Known ALS Genes in an Italian Population-Based Cohort (2020)
  • PMID 32739880 Generation of an induced pluripotent stem cell line, CSSi011-A (6534), from an Amyotrophic lateral sclerosis patient with heterozygous L145F mutation in SOD1 gene (2020)
  • PMID 31747286 An Allosteric Pathway in Copper, Zinc Superoxide Dismutase Unravels the Molecular Mechanism of the G93A Amyotrophic Lateral Sclerosis-Linked Mutation (2019)
  • PMID 29493298 Phenotypic and genotypic studies of ALS cases in ALS-SMA families (2018)
  • PMID 29149916 Whole-exome sequencing in amyotrophic lateral sclerosis suggests NEK1 is a risk gene in Chinese (2017)
  • PMID 28291249 Analysis of SOD1 mutations in a Chinese population with amyotrophic lateral sclerosis: a case-control study and literature review (2017)
  • PMID 27978769 Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center (2016)
  • PMID 30512582 [Epidemiology of amyotrophic lateral sclerosis]. (2016)

References

All PMID-linked papers cited in the evidence network above, deduplicated and sorted by publication year.

  1. PMID 41513843 Demographic, clinical and genetic characteristics of patients with amyotrophic lateral sclerosis from two specialised centres in Austria (2026) B→C
  2. PMID 41852184 High Prevalence of <scp> <i>SOD1</i> </scp> Pathogenic Variants in the <scp>UK</scp> Biobank: Implications for Early Intervention in Amyotrophic Lateral Sclerosis (2026) B→C
  3. PMID 40957416 Landscapes of missense variant impact for human superoxide dismutase 1 (2025) B→C
  4. PMID 40050936 Impact of cysteine mutations on the structural dynamics and functional impairment of SOD1: insights into the pathogenicity of amyotrophic lateral sclerosis (2025) B→C
  5. PMID 40763713 Epidemiology of Amyotrophic Lateral Sclerosis in Western and Northern Finland (2025) B→C
  6. PMID 41276866 Cutting-edge treatments in amyotrophic lateral sclerosis: the role of molecular pathogenesis in targeted therapies (2025) B→C
  7. PMID 41283823 Amyotrophic lateral sclerosis in Saudi Arabia: a multicenter descriptive study (2025) B→C
  8. PMID 41359166 Four families with slowly progressive ALS due to p.Val120Leu SOD1 variant in Northeast Brazil (2025) B→C
  9. PMID 37159497 Advantages of routine next‐generation sequencing over standard genetic testing in the amyotrophic lateral sclerosis clinic (2023) B→C
  10. PMID 34996976 SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity (2022) B→C
  11. PMID 36549973 Genetic landscape of ALS in Malta based on a quinquennial analysis (2022) B→C
  12. PMID 34518333 De novo mutations in <i>SOD1</i> are a cause of ALS (2021) B→C
  13. PMID 33630959 Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis (2021) B→C
  14. PMID 33414559 Genetic analysis of ALS cases in the isolated island population of Malta (2021) B→C
  15. PMID 33208543 Mutational Analysis of Known ALS Genes in an Italian Population-Based Cohort (2020) B→C
  16. PMID 32739880 Generation of an induced pluripotent stem cell line, CSSi011-A (6534), from an Amyotrophic lateral sclerosis patient with heterozygous L145F mutation in SOD1 gene (2020) B→C
  17. PMID 31873138 Ketogenic diet induces skeletal muscle atrophy via reducing muscle protein synthesis and possibly activating proteolysis in mice (2019) A→B
  18. PMID 31747286 An Allosteric Pathway in Copper, Zinc Superoxide Dismutase Unravels the Molecular Mechanism of the G93A Amyotrophic Lateral Sclerosis-Linked Mutation (2019) B→C
  19. PMID 29493298 Phenotypic and genotypic studies of ALS cases in ALS-SMA families (2018) B→C
  20. PMID 29149916 Whole-exome sequencing in amyotrophic lateral sclerosis suggests NEK1 is a risk gene in Chinese (2017) B→C
  21. PMID 28291249 Analysis of SOD1 mutations in a Chinese population with amyotrophic lateral sclerosis: a case-control study and literature review (2017) B→C
  22. PMID 27978769 Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center (2016) B→C
  23. PMID 30512582 [Epidemiology of amyotrophic lateral sclerosis]. (2016) B→C

Limitations & disclaimer

This hypothesis was generated algorithmically through cross-domain literature analysis and has not been experimentally validated. Treat it as a starting point for further investigation, not a therapeutic recommendation. For established knowledge about each entity, refer to the authoritative sources linked above (Wikipedia, DrugBank, UniProt, MeSH).

Related hypotheses

Other hypotheses in the catalog sharing the same drug or mediator.

shared mediator
sodium butyrate → Sod1 → ALS
score 0.383 View in catalog →
shared mediator
LWE → SOD1 → ALS
score 0.383 View in catalog →
shared mediator
saxagliptin → SOD1 → ALS
score 0.383 View in catalog →
How was this hypothesis generated? Read about Robertium's Swanson ABC discovery method View raw data in catalog Open hypothesis #2091 with full evidence and metadata