Revealing third-order interactions through the integration of machine learning and entropy methods in genomic studies
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
BACKGROUND: Non-linear relationships at the genotype level are essential in understanding the genetic interactions of complex disease traits. Genome-wide association Studies (GWAS) have revealed statistical association of the SNPs in many complex diseases. As GWAS results could not thoroughly reveal the genetic background of these disorders, Genome-Wide Interaction Studies have started to gain importance. In recent years, various statistical approaches, such as entropy-based methods, have been suggested for revealing these non-additive interactions between variants. This study presents a novel prioritization workflow integrating two-step Random Forest (RF) modeling and entropy analysis after PLINK filtering. PLINK-RF-RF workflow is followed by an entropy-based 3-way interaction information (3WII) method to capture the hidden patterns resulting from non-linear relationships between genotypes in Late-Onset Alzheimer Disease to discover early and differential diagnosis markers. RESULTS: Three models from different datasets are developed by integrating PLINK-RF-RF analysis and entropy-based three-way interaction information (3WII) calculation method, which enables the detection of the third-order interactions, which are not primarily considered in epistatic interaction studies. A reduced SNP set is selected for all three datasets by 3WII analysis by PLINK filtering and prioritization of SNP with RF-RF modeling, promising as a model minimization approach. Among SNPs revealed by 3WII, 4 SNPs out of 19 from GenADA, 1 SNP out of 27 from ADNI, and 4 SNPs out of 106 from NCRAD are mapped to genes directly associated with Alzheimer Disease. Additionally, several SNPs are associated with other neurological disorders. Also, the genes the variants mapped to in all datasets are significantly enriched in calcium ion binding, extracellular matrix, external encapsulating structure, and RUNX1 regulates estrogen receptor-mediated transcription pathways. Therefore, these functional pathways are proposed for further examination for a possible LOAD association. Besides, all 3WII variants are proposed as candidate biomarkers for the genotyping-based LOAD diagnosis. CONCLUSION: The entropy approach performed in this study reveals the complex genetic interactions that significantly contribute to LOAD risk. We benefited from the entropy-based 3WII as a model minimization step and determined the significant 3-way interactions between the prioritized SNPs by PLINK-RF-RF. This framework is a promising approach for disease association studies, which can also be modified by integrating other machine learning and entropy-based interaction methods.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it