Novel Pooling Strategies for Genetic Testing, with Application to Newborn Screening
Bibliographic record
Abstract
Newborn screening (NBS) is a state-level initiative that detects life-threatening genetic disorders for which early treatment can substantially improve health outcomes. Cystic fibrosis (CF) is among the most prevalent disorders in NBS. CF can be caused by a large number of mutation variants to the CFTR gene. Most states use a multitest CF screening process that includes a genetic test (DNA). However, due to cost concerns, DNA is used only on a small subset of newborns (based on a low-cost biomarker test with low classification accuracy), and only for a small subset of CF-causing variants. To overcome the cost barriers of expanded genetic testing, we explore a novel approach, of multipanel pooled DNA testing. This approach leads not only to a novel optimization problem (variant selection for screening, variant partition into multipanels, and pool size determination for each panel), but also to novel CF NBS processes. We establish key structural properties of optimal multipanel pooled DNA designs; develop a methodology that generates a family of optimal designs at different costs; and characterize the conditions under which a 1-panel versus a multipanel design is optimal. This methodology can assist decision-makers to design a screening process, considering the cost versus accuracy trade-off. Our case study, based on published CF NBS data from the state of New York, indicates that the multipanel and pooling aspects of genetic testing work synergistically, and the proposed NBS processes have the potential to substantially improve both the efficiency and accuracy of current practices. This paper was accepted by Stefan Scholtes, healthcare management. Funding: This work was supported by National Science Foundation [Grant 1761842]. Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. Supplemental Material: The data files and e-companion are available at https://doi.org/10.1287/mnsc.2021.4289 .
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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 | 0.012 | 0.029 |
| Meta-epidemiology (narrow) | 0.003 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".