Modifier genes in Mendelian disorders: the example of hemoglobin disorders
Bibliographic record
Abstract
The disorders of hemoglobin, including sickle cell disease (SCD) and β-thalassemia, are the most common "Mendelian" genetic diseases in the world. Numerous studies have demonstrated the complexity in making genotype-phenotype correlations in both SCD and β-thalassemia. Indeed, patients with exactly the same set of pathogenic globin mutations can have dramatically variable clinical courses. We discuss natural history studies that have attempted to delineate the factors responsible for the variability among the numerous clinical complications noted in these diseases. We then discuss, in depth, two well characterized ameliorating factors in the β-hemoglobin disorders, concomitant α-thalassemia, and elevated levels of fetal hemoglobin (HbF). We use the study of HbF regulation to illustrate how important insights into the genetic modifiers in Mendelian diseases can be achieved through the study of such factors. We finally go on to discuss future avenues of research that may allow us to gain further insight into the poorly understood clinical heterogeneity of this fascinating set of common genetic diseases.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.003 | 0.003 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.003 |
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".