A191 NEXT GENERATION SEQUENCING IN THE INVESTIGATION OF HYPERFERRITINEMIA
Bibliographic record
Abstract
Hyperferritinemia is common and often suggests the diagnosis of iron overload. However, many times it is elevated secondary to inflammation, obesity, alcohol use, or unknown causes. Most Caucasian patients with iron overload are homozygotes for the C282Y mutation of the HFE gene. There are a growing number of iron related genes that may contribute to an elevated ferritin and iron overload. To design a next generation sequencing platform to assess for genetic mutations in 15 iron genes as a diagnostic tool in the investigation of hyperferritinema. Libraries were sequenced using the MiSeq v2 reagent kit to generate 2 x 150 bp paired-end reads using the MiSeq fastq generation mode (Illumina, San Diego, CA), with 24 different patient samples multiplexed per run. Sequence analysis for variant identification, alignment and coverage distribution was performed with NextGene software v2.4.1 (SoftGenetics, LLC, State College, PA) using standard alignment settings (allowable mismatch bases: 1; allowable ambiguous alignments: 50; seeds bases: 30; move step bases: 5; allowable alignments: 100; matching base percentage > 85%). BAM and VCF files were imported into Geneticist Assistant v1.1.5 (SoftGenetics, LLC; State College, PA) for quality control assessment (minimum base coverage; mean exon coverage). The methodology also will assess copy number variation and does not require MLPA confirmation. Genes analyzed included HFE, HJV, HAMP,TfR2,FTL,CP,SLC40A1. Patients were selected from the referral practice at a tertiary care hospital with elevations in serum ferritin > 1000 ug/L who were not typical C282Y homozygotes. There were 120 patients selected for analysis. There were 6 patients homozygous for HJV mutations (G320V in 2 unrelated, and Leu366Ter in 4 related). There were 3 FTL mutations detected in patients with cataracts and heterozygous mutations found in HAMP, CP, TfR2, and TF genes. Next generation sequencing provides a platform to rapidly test for HFE and many other mutations in selected cases. Funding has been requested to provide this analysis for selected Ontario cases similar to funded genetic panels for other rare genetic diseases. None
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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 | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
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".