Artificial intelligence, explainability, and the scientific method: A proof-of-concept study on novel retinal biomarker discovery
Bibliographic record
Abstract
Abstract We present a structured approach to combine explainability of artificial intelligence (AI) with the scientific method for scientific discovery. We demonstrate the utility of this approach in a proof-of-concept study where we uncover biomarkers from a convolutional neural network (CNN) model trained to classify patient sex in retinal images. This is a trait that is not currently recognized by diagnosticians in retinal images, yet, one successfully classified by CNNs. Our methodology consists of four phases: In Phase 1, CNN development, we train a visual geometry group (VGG) model to recognize patient sex in retinal images. In Phase 2, Inspiration, we review visualizations obtained from post hoc interpretability tools to make observations, and articulate exploratory hypotheses. Here, we listed 14 hypotheses retinal sex differences. In Phase 3, Exploration, we test all exploratory hypotheses on an independent dataset. Out of 14 exploratory hypotheses, nine revealed significant differences. In Phase 4, Verification, we re-tested the nine flagged hypotheses on a new dataset. Five were verified, revealing (i) significantly greater length, (ii) more nodes, and (iii) more branches of retinal vasculature, (iv) greater retinal area covered by the vessels in the superior temporal quadrant, and (v) darker peripapillary region in male eyes. Finally, we trained a group of ophthalmologists (N=26) to recognize the novel retinal features for sex classification. While their pretraining performance was not different from chance level or the performance of a nonexpert group (N=31), after training, their performance increased significantly (p<0.001, d=2.63). These findings showcase the potential for retinal biomarker discovery through CNN applications, with the added utility of empowering medical practitioners with new diagnostic capabilities to enhance their clinical toolkit.
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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 | 0.021 | 0.041 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.002 | 0.003 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".