Journal Article
Machine Learning

Deep learning-based transformation of H&E stained tissues into special stains

Kevin de Haan(California NanoSystems Institute), Yijie Zhang(California NanoSystems Institute), Jonathan E. Zuckerman(University of California, Los Angeles), Tairan Liu(California NanoSystems Institute), Anthony Sisk(University of California, Los Angeles), Miguel F. Diaz(Kaiser Permanente), Kuang‐Yu Jen(University of California, Davis), Alexander Nobori(University of California, Los Angeles), Sofia Liou(University of California, Los Angeles), Sarah Zhang(University of California, Los Angeles), Rana Riahi(University of California, Los Angeles), Yair Rivenson(California NanoSystems Institute), William D. Wallace(Keck Hospital of USC), Aydogan Özcan(California NanoSystems Institute)
August 12, 2021Nature Communications317 citations

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Nature Communications

Venue

2021

Year

Abstract

Pathology is practiced by visual inspection of histochemically stained tissue slides. While the hematoxylin and eosin (H&E) stain is most commonly used, special stains can provide additional contrast to different tissue components. Here, we demonstrate the utility of supervised learning-based computational stain transformation from H&E to special stains (Masson's Trichrome, periodic acid-Schiff and Jones silver stain) using kidney needle core biopsy tissue sections. Based on the evaluation by three renal pathologists, followed by adjudication by a fourth pathologist, we show that the generation of virtual special stains from existing H&E images improves the diagnosis of several non-neoplastic kidney diseases, sampled from 58 unique subjects (P = 0.0095). A second study found that the quality of the computationally generated special stains was statistically equivalent to those which were histochemically stained. This stain-to-stain transformation framework can improve preliminary diagnoses when additional special stains are needed, also providing significant savings in time and cost.

Analysis

Why This Paper Matters

This paper addresses a critical bottleneck in pathology: the need for multiple special stains to diagnose non-neoplastic kidney diseases. Traditional histochemical staining is time-consuming, costly, and requires additional tissue sections. By demonstrating that deep learning can generate high-quality virtual special stains directly from routine H&E images, the authors provide a practical solution that could streamline clinical workflows and reduce turnaround times. The rigorous evaluation by multiple pathologists and statistical significance testing (P = 0.0095) lend credibility to the approach, making it a strong candidate for clinical adoption.

Technical Contributions

The key innovation is the use of a supervised deep learning model to perform stain-to-stain transformation. The model learns a mapping from H&E to three special stains (Masson's Trichrome, periodic acid-Schiff, and Jones silver stain) using paired tissue sections. This is a challenging task because the stains highlight different tissue components (e.g., collagen, glycogen, basement membranes) and the model must capture subtle morphological differences. The authors also conducted a rigorous clinical validation study with multiple pathologists, which is rare in computational pathology research. The statistical equivalence test between virtual and real special stains further strengthens the technical contribution.

Results

The primary result is that virtual special stains improved the diagnosis of non-neoplastic kidney diseases compared to using H&E alone, with a P-value of 0.0095. A second study found that the quality of computationally generated special stains was statistically equivalent to histochemically stained ones. These results are based on 58 unique subjects and evaluation by three renal pathologists, with adjudication by a fourth. The study also highlights significant time and cost savings, as virtual stains can be generated in seconds without additional tissue processing.

Significance

This work advances the field of computational pathology by showing that deep learning can not only replicate but also enhance traditional staining methods. It opens the door to virtual staining for other tissue types and stains, potentially reducing the need for multiple physical sections and reagents. For AI practitioners, the paper demonstrates a successful application of supervised learning in a high-stakes medical domain, with a validation framework that could serve as a template for future studies. The approach also has implications for resource-limited settings where access to special stains is restricted.