Derivation of pediatric reference intervals for vitamin B-12 biomarkers and comparison of their diagnostic ability in children at risk of vitamin B-12 deficiency
Bibliographic record
Abstract
Background: Early detection of vitamin B-12 (B-12) deficiency through reliable biomarkers is critical to prevent poor development and life-long health consequences. Children with short bowel syndrome (SBS) are at risk of B-12 deficiency. Serum total B-12 is the most commonly used B-12 biomarker but there is ambiguity to its performance. Holotranscobalamin (holoTC), the B-12 form taken up by cells, may be a more sensitive biomarker. Methylmalonic acid (MMA) is a functional and sensitive biomarker, but lacks availability in clinical laboratories. Overall, the utility of B-12 biomarkers in the pediatric population is limited, in part due to the lack of age-specific cutoffs. Objectives: 1) To derive age- and sex-specific reference intervals for serum holoTC and MMA concentrations in healthy children, and 2) to compare the diagnostic ability of total B-12 and holoTC to detect functional B-12 deficiency in pediatric SBS patients. Methods: The project consisted of 1) the secondary analysis of bio-banked serum samples for MMA and holoTC from 337 healthy Canadian children aged 0-18 years, and of 2) a descriptive, prospective study with 26 SBS patients from the BC Children’s Hospital in Vancouver, BC. Clinical and dietary data, and blood samples for quantitation of B-12 biomarkers, were collected over 2 years. Results: 1) Age-group partitions but no sex partitions were identified for MMA and holoTC. Upper reference limits (97.5th percentiles) for MMA were calculated for infants aged 0-<1 year and children aged 1-<19 years, and lower reference limits for holoTC were estimated for infants aged 0-<1 year, children aged 1-<14 years and adolescents aged 14-<19 years. 2) The diagnostic ability to detect functional B-12 deficiency was higher for holoTC compared to total B-12. HoloTC identified 4 out of 5 cases and total B-12 identified 1 of 5 cases of elevated MMA in our cohort of children with SBS. Conclusion: This is the first study to provide age-specific reference intervals for serum MMA and holoTC, that are required given the high variability of MMA and holoTC concentration across childhood. Serum holoTC may be a more reliable indicator than serum total B-12 at identifying functional B-12 deficiency in children with SBS.
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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 | 0.005 | 0.010 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.003 | 0.003 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".