P409: Clinical utility of genomic sequencing for hereditary cancer syndromes: An observational chart review
Bibliographic record
Abstract
management approaches for hundreds of additional genetic disorders are available.Efforts such as the NIH-funded BabySeq Project explore the implications of genomic sequencing in healthy infants with the aim of designing strategies for implementation.Methods: We designed an online survey for rare disease experts (n = 389), investigating which additional treatable genetic conditions (currently not included on the RUSP) they recommend for screening in newborns using genomic sequencing.A list of 649 genes associated with treatable genetic conditions in 13 clinical areas was designed.Participants were invited to assess all proposed genes or to select the clinical area with which they were most familiar.We analyzed concordance among experts regarding screening specific genes in newborns.We also assessed responses to a series of descriptive questions about participant attitudes regarding universal genomic sequencing to screen newborns for treatable genetic disorders as well as the inclusion of disorders that are untreatable, lack confirmatory orthogonal tests, are of low penetrance, or are adult-onset.Results: A total of 238 (61.2%) experts, including directors of genetics and genomics programs accredited by the Accreditation Council for Graduate Medical Education (n = 64), physicians specializing in the care of rare disease patients (n = 165), and senior scientists within pharmaceutical companies specializing in rare disease therapeutics (n = 9) participated.Experts agreed with ≥85% concordance that 25 genes associated with disorders not currently included in universal NBS programs should be evaluated in presymptomatic infants (OTC, G6PC, SLC37A4, CYP11B1, ARSB, F8, F9, SLC2A1, CYP17A1, RB1, IDS, GUSB, DMD, GLUD1, CYP11A1, GALNS, CPS1, PLPBP, ALDH7A1, SLC26A3, SLC25A15, SMPD1, GATM, SLC7A7, NAGS).Orthogonal tests are available for confirmation of genetic disorders caused by 24 out of these 25 genes (96%).Clinical areas of interest included Metabolism, Neurology, Endocrinology and Hemato-Oncology.A total of 42 genes had ≥80% concordance and 432 genes had ≥50% concordance.Overall, 161 of 183 (87.9%) experts agreed or somewhat agreed that genomic sequencing should be used to expand the number of conditions included in NBS.Conclusion: While several of these genes are associated with clinical domains that are currently included in NBS, there are multiple candidates that represent new frontiers for NBS, such as hereditary cancer predisposition syndromes.This study highlights that experts endorse the expansion of NBS programs to include additional treatable monogenic disorders, including 25 high-priority conditions which could be efficiently screened using genomic sequencing.
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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 | 0.009 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".