Two‐stage subgroup‐specific time‐to‐event (2S‐Sub‐TITE): An adaptive two‐stage time‐to‐toxicity design for subgroup‐specific dose finding in phase I oncology trials
Bibliographic record
Abstract
For phase I trials, the subgroup-specific time-to-event (Sub-TITE) design identifies the maximum tolerated dose (MTD) separately in 2+ heterogeneous patient subgroups. Sub-TITE allows borrowing strength and dynamic clustering across subgroups from the trial's start, but delaying the initiation of borrowing and clustering may improve trial accuracy. We propose the 2-stage Sub-TITE (2S-Sub-TITE) design in which the trial starts by estimating separate models per subgroup, and then initiates the Sub-TITE design at some pre-specified point of patient accrual. We evaluate the operating characteristics of the 2S-Sub-TITE design using simulations. Nine configurations of the 2S-Sub-TITE design (varying in timing of initiation of borrowing/clustering and prior probability of subgroup heterogeneity, p_hetero) and three control methods were compared across 1000 randomly-generated true toxicity probability scenarios. Effects of priors, sample size, escalation rules, target toxicity probability, accrual rate, and number of subgroups were evaluated. Metrics included: proportion of correct selection (PCS) of the true MTD, and average number of toxicities incurred. Among the 5 2S-Sub-TITE configurations (out of 9 total) with the highest PCS (45%) when the subgroup heterogeneity assumption is correct (all of which out-perform the control methods by 2%-6%), the configuration which enables borrowing and clustering allowance with p_hetero = 0.7 starting at 75% patient accrual best minimizes toxicities as well as losses in accuracy if the heterogeneity assumption is incorrect. For trials with high confidence in subgroup heterogeneity, the 2S-Sub-TITE configuration enabling borrowing/clustering with p_hetero = 0.7 starting at 75% patient accrual exhibits superior dose-finding accuracy compared to existing methods.
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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 | 0.053 | 0.067 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.003 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.003 | 0.003 |
| Insufficient payload (model declined to judge) | 0.007 | 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".