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
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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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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.038 | 0.060 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.004 | 0.001 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.028 | 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 it