Penalized likelihood ratio test for a biomarker threshold effect in clinical trials based on generalized linear models
Bibliographic record
Abstract
Abstract In a clinical trial, the responses to the new treatment may vary among patient subsets with different characteristics in a biomarker. It is often necessary to examine whether there is a cutpoint for the biomarker that divides the patients into two subsets of those with more favourable and less favourable responses. More generally, we approach this problem as a test of homogeneity in the effects of a set of covariates in generalized linear regression models. The unknown cutpoint results in a model with nonidentifiability and a nonsmooth likelihood function to which the ordinary likelihood methods do not apply. We first use a smooth continuous function to approximate the indicator function defining the patient subsets. We then propose a penalized likelihood ratio test to overcome the model irregularities. Under the null hypothesis, we prove that the asymptotic distribution of the proposed test statistic is a mixture of chi‐squared distributions. Our method is based on established asymptotic theory, is simple to use, and works in a general framework that includes logistic, Poisson, and linear regression models. In extensive simulation studies, we find that the proposed test works well in terms of size and power. We further demonstrate the use of the proposed method by applying it to clinical trial data from the Digitalis Investigation Group (DIG) on heart failure.
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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 | 0.107 | 0.345 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.004 | 0.003 |
| Bibliometrics | 0.004 | 0.003 |
| Science and technology studies | 0.001 | 0.004 |
| Scholarly communication | 0.002 | 0.003 |
| Open science | 0.004 | 0.003 |
| Research integrity | 0.003 | 0.003 |
| Insufficient payload (model declined to judge) | 0.006 | 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".