A pilot study to investigate the clinically predictive values of copy number variations detected by next-generation sequencing of cell-free deoxyribonucleic acid in spent culture media
Bibliographic record
Abstract
Objective Analysis of cell free DNA in spent culture media has been identified as a non-invasive alternative to trophectoderm biopsy for PGT-A. However, the clinical value has not been well studied. We performed a pilot study with the primary interest of estimating the positive predictive value of copy number variations to predict nonviable or aneuploid embryos and investigate the false positive risk. Design Diagnostic/prognostic accuracy study. Subjects Patients aged 35 and younger with an indication for IVF-ICSI and elective single frozen embryo transfer at a single, private IVF centre. Intervention Embryo selection was performed according to conventional grading, blinded to non-invasive PGT-A results. After clinical outcomes were established, spent culture media samples were analyzed. Main outcome measures Prognostic accuracy of copy number variations according to niPGT-A results to predict nonviability or clinical aneuploidy. Results One-hundred twenty patients completed the study. Interpretations of NGS profiles were as follows: 7.5% (n=9) failed quality control; 62.5% (n=75) no copy number variations detected; 30% (n=36) abnormal copy number detected. Stratification of abnormal NGS profiles were as follows: 15% (n=18) whole chromosome; 15% (n=18) uncertain reproductive potential. Intermediate copy number variation was evident in 27.8% (n=5) of the whole chromosome abnormalities. Negative predictive value for samples with no detected abnormality was 57.3% (43/75). Whole chromosome abnormality was associated with a positive predictive value of 94.4% (17/18), lower sustained implantation rate (5.6%, 1/18), and higher relative risk for nonviability compared to no detected abnormalities (RR 2.21, 95% CI:1.66-2.94) (p<0.001). No other copy number variations were associated with significant differences in sustained implantation or relative risks for nonviability. Unequal sex chromosome proportions suggested that maternal contamination was not uncommon. A secondary descriptive analysis of 705 supernumerary embryos revealed proportions of NGS profile interpretations similar to the transferred cohort. Significant differences in MAPD between certain subcategories of CNV abnormalities were apparent. Conclusion Whole chromosome abnormalities were associated with high positive predictive value and significant relative risk for nonviability. Embryos associated with other copy number variations had sustained implantation rates similar to those with no abnormalities detected. Further studies are required to validate the clinical applicability of non-invasive PGT-A. Analysis of cell free DNA in spent culture media has been identified as a non-invasive alternative to trophectoderm biopsy for PGT-A. However, the clinical value has not been well studied. We performed a pilot study with the primary interest of estimating the positive predictive value of copy number variations to predict nonviable or aneuploid embryos and investigate the false positive risk. Diagnostic/prognostic accuracy study. Patients aged 35 and younger with an indication for IVF-ICSI and elective single frozen embryo transfer at a single, private IVF centre. Embryo selection was performed according to conventional grading, blinded to non-invasive PGT-A results. After clinical outcomes were established, spent culture media samples were analyzed. Prognostic accuracy of copy number variations according to niPGT-A results to predict nonviability or clinical aneuploidy. One-hundred twenty patients completed the study. Interpretations of NGS profiles were as follows: 7.5% (n=9) failed quality control; 62.5% (n=75) no copy number variations detected; 30% (n=36) abnormal copy number detected. Stratification of abnormal NGS profiles were as follows: 15% (n=18) whole chromosome; 15% (n=18) uncertain reproductive potential. Intermediate copy number variation was evident in 27.8% (n=5) of the whole chromosome abnormalities. Negative predictive value for samples with no detected abnormality was 57.3% (43/75). Whole chromosome abnormality was associated with a positive predictive value of 94.4% (17/18), lower sustained implantation rate (5.6%, 1/18), and higher relative risk for nonviability compared to no detected abnormalities (RR 2.21, 95% CI:1.66-2.94) (p<0.001). No other copy number variations were associated with significant differences in sustained implantation or relative risks for nonviability. Unequal sex chromosome proportions suggested that maternal contamination was not uncommon. A secondary descriptive analysis of 705 supernumerary embryos revealed proportions of NGS profile interpretations similar to the transferred cohort. Significant differences in MAPD between certain subcategories of CNV abnormalities were apparent. Whole chromosome abnormalities were associated with high positive predictive value and significant relative risk for nonviability. Embryos associated with other copy number variations had sustained implantation rates similar to those with no abnormalities detected. Further studies are required to validate the clinical applicability of non-invasive PGT-A.
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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 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| 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".