Phenotypic Evaluation of a Family Cohort with Hemolytic Anemia
Bibliographic record
Abstract
Abstract Abstract 3214 Background: We have identified a kindred in Manitoba and Saskatchewan, Canada, affected by non-immune hemolytic anemia. Red cell morphology, an elevated MCHC and decreased osmotic fragility are consistent with hereditary xerocytosis, a rare hemolytic disorder, for which the causative genetic mutation is unknown. Objectives: To describe the clinical phenotype and inheritance of an uncharacterized chronic hemolytic disorder in a large kindred. Methods: With assistance from each consenting family member, a pedigree was constructed. A focused history was taken and the presence of splenomegaly was assessed by physical examination. Laboratory analysis included a CBC, reticulocyte count, osmotic fragility and peripheral blood film. Biochemical measurements of LDH, ALT, bilirubin, ferritin, haptoglobin, plasma hemoglobin and methemoglobin were performed. Glycolytic enzymes were evaluated in a subset of patients to rule out other rare causes of hemolysis. Results: The family pedigree captured the genetic relations of 342 individuals spanning 5 generations. Consent to participate in the detailed family study was obtained from 137 family members. The average age of the study population was 29 years (range 8 months to 76 years). Laboratory specimens were collected from 26 unrelated spouses and 111 related individuals. Males represented 48% of the studied population. The distribution of reticulocyte counts was distinctly bimodal with no overlap between the two populations, allowing classification of individuals as phenotypically affected or non-affected. The mean percent reticulocyte count of non-affected subjects (related family members and unrelated spouses) was 1.1% (± 0.4, range 0.5–2.3%). Affected subjects had a mean percent reticulocyte count of 9.7% (± 2.6, range 5.3–14.6%). Using this classification, the hemolytic process segregated in an autosomal dominant fashion with complete penetrance. A history of anemia (46 vs. 8%), jaundice (45 vs. 4%), red or brown urine (45 vs. 1%), and either gallstones or cholecystectomy (41 vs. 4%) was more prevalent in affected than unaffected individuals. Episodes of anemia tended to be associated with illness or stress. There was no association between the hemolytic phenotype and neuromuscular, cardiovascular, pulmonary, renal, hepatic, or endocrine disorders. Despite a mean percent reticulocyte count of 9.7% in affected individuals, the mean hemoglobin concentration was not statistically different between affected and unaffected individuals (13.5 ± 1.2 g/dL vs. 13.8 ± 1.4 g/dL, p=0.26). The MCV (96.7 ± 5.5 fL vs. 87.3 ± 5.2 fL, p<0.01) and MCHC (36.6 ± 0.6 g/dL vs. 33.8 ± 0.9 g/dL, p<0.01) were significantly elevated among affected individuals. Morphologically, target cells and stomatocytes were increased among affected individuals. Affected individuals had significantly elevated indirect bilirubin and decreased haptoglobin compared to unaffected or unrelated individuals. Serum ferritin was elevated in all age tertiles in affected individuals compared to non-affected or unrelated individuals, and 7/29 affected individuals had a serum ferritin >900 μg/L. Osmotic fragility performed on 4 affected individuals was decreased. Glycolytic enzymes, screens for unstable hemoglobins and hemoglobinopathies were normal in those tested. Conclusions: In this family study, elevated percent reticulocyte counts were used to characterize the presence of a well compensated, autosomal dominant hemolytic process associated with an elevated MCHC and decreased osmotic fragility. Clinically this condition is associated with gallstones and progressive iron loading. Features are consistent with hereditary xerocytosis. Molecular analysis is currently underway to locate the causative gene and identify the underlying mutation. Disclosures: No relevant conflicts of interest to declare.
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How this classification was reachedexpand
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 | 0.000 | 0.000 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".