Evaluation of a Gene Expression-Based Machine Learning Classifier to Discriminate Normal from Cancer Gastric Organoids
Bibliographic record
Abstract
Three-dimensional cell model systems such as tumour organoids allow for in vitro modelling of self-organized tissue with functional and histologic similarity to in vivo tissue. However, there is a need for standard protocols and techniques to confirm the presence of cancer within organoids derived from tumour tissue. The aim of this study was to assess the utility of a Nanostring gene expression-based machine learning classifier to determine the presence of cancer or normal organoids in cultures developed from both benign and cancerous stomach biopsies. A prospective cohort of normal and cancer stomach biopsies were collected from 2019 to 2022. Tissue specimens were processed for formalin-fixed paraffin-embedding (FFPE) and a subset of specimens were established in organoid cultures. Specimens were labelled as normal or cancer according to analysis of the FFPE tissue by two pathologists. The gene expression in FFPE and organoid tissue was measured using a 107 gene Nanostring codeset and normalized using the Removal of Unwanted Variation III algorithm. Our machine learning model was developed using five-fold nested cross-validation to classify normal or cancer gastric tissue from publicly available Asian Cancer Research Group (ACRG) gene expression data. The models were externally validated using the Cancer Genome Atlas (TCGA), as well as our own FFPE and organoid gene expression data. A total of 60 samples were collected, including 38 cancer FFPE specimens, 5 normal FFPE specimens, 12 cancer organoids, and 5 normal organoids. The optimal model design used a Least Absolute Shrinkage and Selection Operator model for feature selection and an ElasticNet model for classification, yielding area under the curve (AUC) values of 0.99 [95% CI: 0.99–1], 0.90 [95% CI: 0.87–0.93], and 0.79 [95% CI: 0.74–0.84] for ACRG (internal test), FFPE, and organoid (external test) data, respectively. The performance of our final model on external data achieved AUC values of 0.99 [95% CI: 0.98–1], 0.94 [95% CI: 0.86–1], and 0.85 [95% CI: 0.63–1] for TCGA, FFPE, and organoid specimens, respectively. Using a public database to create a machine learning model in combination with a Nanostring gene expression assay allows us to allocate organoids and their paired whole tissue samples. This platform yielded reasonable accuracy for FFPE and organoid specimens, with the former being more accurate. This study re-affirms that although organoids are a high-fidelity model, there are still limitations in validating the recapitulation of cancer in vitro.
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How this classification was reachedexpand
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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 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 teacher head, 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".