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Article ; Online: High-throughput whole-slide scanning to enable large-scale data repository building.

Zarella, Mark D / Rivera Alvarez, Keysabelis

2022 Volume 257, Issue 4, Page(s) 383–390

Abstract: Digital pathology and artificial intelligence (AI) rely on digitization of patient material as a necessary first step. AI development benefits from large sample sizes and diverse cohorts, and therefore efforts to digitize glass slides must meet these ... ...

Abstract	Digital pathology and artificial intelligence (AI) rely on digitization of patient material as a necessary first step. AI development benefits from large sample sizes and diverse cohorts, and therefore efforts to digitize glass slides must meet these needs in an efficient and cost-effective manner. Technical innovation in whole-slide imaging has enabled high-throughput slide scanning through the coordinated increase in scanner capacity, speed, and automation. Combining these hardware innovations with automated informatics approaches has enabled more efficient workflows and the opportunity to provide higher-quality imaging data using fewer personnel. Here we review several practical considerations for deploying high-throughput scanning and we present strategies to increase efficiency with a focus on quality. Finally, we review remaining challenges and issue a call to vendors to innovate in the areas of automation and quality control in order to make high-throughput scanning realizable to laboratories with limited resources. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
MeSH term(s)	Artificial Intelligence ; Humans ; Microscopy/methods ; United Kingdom ; Workflow
Language	English
Publishing date	2022-06-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.5923
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Article: Video compression to support the expansion of whole-slide imaging into cytology.

Zarella, Mark D / Jakubowski, Jennifer

Journal of medical imaging (Bellingham, Wash.)

2019 Volume 6, Issue 4, Page(s) 47502

Abstract: Digital screening and diagnosis from cytology slides can be aided by capturing multiple focal planes. However, using conventional methods, the large file sizes of high-resolution whole-slide images increase linearly with the number of focal planes ... ...

Abstract	Digital screening and diagnosis from cytology slides can be aided by capturing multiple focal planes. However, using conventional methods, the large file sizes of high-resolution whole-slide images increase linearly with the number of focal planes acquired, leading to significant data storage and bandwidth requirements for the efficient storage and transfer of cytology virtual slides. We investigated whether a sequence of focal planes contained sufficient redundancy to efficiently compress virtual slides across focal planes by applying a commonly available video compression standard, high-efficiency video coding (HEVC). By developing an adaptive algorithm that applied compression to achieve a target image quality, we found that the compression ratio of HEVC exceeded that obtained using JPEG and JPEG2000 compression while maintaining a comparable level of image quality. These results suggest an alternative method for the efficient storage and transfer of whole-slide images that contain multiple focal planes, expanding the utility of this rapidly evolving imaging technology into cytology.
Language	English
Publishing date	2019-12-19
Publishing country	United States
Document type	Journal Article
ISSN	2329-4302
ISSN	2329-4302
DOI	10.1117/1.JMI.6.4.047502
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Article: Laboratory Computer Performance in a Digital Pathology Environment: Outcomes from a Single Institution.

Zarella, Mark D / Feldscher, Adam

Journal of pathology informatics

2018 Volume 9, Page(s) 44

Abstract: Background: In an effort to provide improved user experience and system reliability at a moderate cost, our department embarked on targeted upgrades of a total of 87 computers over a period of 3 years. Upgrades came in three forms: (i) replacement of ... ...

Abstract	Background: In an effort to provide improved user experience and system reliability at a moderate cost, our department embarked on targeted upgrades of a total of 87 computers over a period of 3 years. Upgrades came in three forms: (i) replacement of the computer with newer architecture, (ii) replacement of the computer's hard drive with a solid-state drive (SSD), or (iii) replacement of the computer with newer architecture and a SSD. Methods: We measured the impact of each form of upgrade on a set of pathology-relevant tasks that fell into three categories: standard use, whole-slide navigation, and whole-slide analysis. We used time to completion of a task as the primary variable of interest. Results: We found that for most tasks, the SSD upgrade had a greater impact than the upgrade in architecture. This effect was especially prominent for whole-slide viewing, likely due to the way in which most whole-slide viewers cached image tiles. However, other tasks, such as whole-slide image analysis, often relied less on disk input or output and were instead more sensitive to the computer architecture. Conclusions: Based on our experience, we suggest that SSD upgrades are viewed in some settings as a viable alternative to complete computer replacement and recommend that computer replacements in a digital pathology setting are accompanied by an upgrade to SSDs.
Language	English
Publishing date	2018-12-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2579241-6
ISSN	2153-3539 ; 2229-5089
ISSN (online)	2153-3539
ISSN	2229-5089
DOI	10.4103/jpi.jpi_47_18
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Article: Contextual modulation revealed by optical imaging exhibits figural asymmetry in macaque V1 and V2.

Zarella, Mark D / Ts'o, Daniel Y

Eye and brain

2017 Volume 9, Page(s) 1–12

Abstract: Neurons in early visual cortical areas are influenced by stimuli presented well beyond the confines of their classical receptive fields, endowing them with the ability to encode fine-scale features while also having access to the global context of the ... ...

Abstract	Neurons in early visual cortical areas are influenced by stimuli presented well beyond the confines of their classical receptive fields, endowing them with the ability to encode fine-scale features while also having access to the global context of the visual scene. This property can potentially define a role for the early visual cortex to contribute to a number of important visual functions, such as surface segmentation and figure-ground segregation. It is unknown how extraclassical response properties conform to the functional architecture of the visual cortex, given the high degree of functional specialization in areas V1 and V2. We examined the spatial relationships of contextual activations in macaque V1 and V2 with intrinsic signal optical imaging. Using figure-ground stimulus configurations defined by orientation or motion, we found that extraclassical modulation is restricted to the cortical representations of the figural component of the stimulus. These modulations were positive in sign, suggesting a relative enhancement in neuronal activity that may reflect an excitatory influence. Orientation and motion cues produced similar patterns of activation that traversed the functional subdivisions of V2. The asymmetrical nature of the enhancement demonstrated the capacity for visual cortical areas as early as V1 to contribute to figure-ground segregation, and the results suggest that this information can be extracted from the population activity constrained only by retinotopy, and not the underlying functional organization.
Language	English
Publishing date	2017-04-11
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2587460-3
ISSN	1179-2744
ISSN	1179-2744
DOI	10.2147/EB.S105609
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Article: Artificial intelligence and digital pathology: clinical promise and deployment considerations.

Zarella, Mark D / McClintock, David S / Batra, Harsh / Gullapalli, Rama R / Valante, Michael / Tan, Vivian O / Dayal, Shubham / Oh, Kei Shing / Lara, Haydee / Garcia, Chris A / Abels, Esther

Journal of medical imaging (Bellingham, Wash.)

2023 Volume 10, Issue 5, Page(s) 51802

Abstract: Artificial intelligence (AI) presents an opportunity in anatomic pathology to provide quantitative objective support to a traditionally subjective discipline, thereby enhancing clinical workflows and enriching diagnostic capabilities. AI requires access ... ...

Abstract	Artificial intelligence (AI) presents an opportunity in anatomic pathology to provide quantitative objective support to a traditionally subjective discipline, thereby enhancing clinical workflows and enriching diagnostic capabilities. AI requires access to digitized pathology materials, which, at present, are most commonly generated from the glass slide using whole-slide imaging. Models are developed collaboratively or sourced externally, and best practices suggest validation with internal datasets most closely resembling the data expected in practice. Although an array of AI models that provide operational support for pathology practices or improve diagnostic quality and capabilities has been described, most of them can be categorized into one or more discrete types. However, their function in the pathology workflow can vary, as a single algorithm may be appropriate for screening and triage, diagnostic assistance, virtual second opinion, or other uses depending on how it is implemented and validated. Despite the clinical promise of AI, the barriers to adoption have been numerous, to which inclusion of new stakeholders and expansion of reimbursement opportunities may be among the most impactful solutions.
Language	English
Publishing date	2023-07-31
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2329-4302
ISSN	2329-4302
DOI	10.1117/1.JMI.10.5.051802
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Article: BCL-2 expression aids in the immunohistochemical prediction of the Oncotype DX breast cancer recurrence score.

Zarella, Mark D / Heintzelman, Rebecca C / Popnikolov, Nikolay K / Garcia, Fernando U

BMC clinical pathology

2018 Volume 18, Page(s) 14

Abstract: Background: The development of molecular techniques to estimate the risk of breast cancer recurrence has been a significant addition to the suite of tools available to pathologists and breast oncologists. It has previously been shown that ... ...

Abstract	Background: The development of molecular techniques to estimate the risk of breast cancer recurrence has been a significant addition to the suite of tools available to pathologists and breast oncologists. It has previously been shown that immunohistochemistry can provide a surrogate measure of tumor recurrence risk, effectively providing a less expensive and more rapid estimate of risk without the need for send-out. However, concordance between gene expression-based and immunohistochemistry-based approaches has been modest, making it difficult to determine when one approach can serve as an adequate substitute for the other. We investigated whether immunohistochemistry-based methods can be augmented to provide a useful therapeutic indicator of risk. Methods: We studied whether the Oncotype DX breast cancer recurrence score can be predicted from routinely acquired immunohistochemistry of breast tumor histology. We examined the effects of two modifications to conventional scoring measures based on ER, PR, Ki-67, and Her2 expression. First, we tested a mathematical transformation that produces a more diagnostic-relevant representation of the staining attributes of these markers. Second, we considered the expression of BCL-2, a complex involved in regulating apoptosis, as an additional prognostic marker. Results: We found that the mathematical transformation improved concordance rates over the conventional scoring model. By establishing a measure of prediction certainty, we discovered that the difference in concordance between methods was even greater among the most certain cases in the sample, demonstrating the utility of an accompanying measure of prediction certainty. Including BCL-2 expression in the scoring model increased the number of breast cancer cases in the cohort that were considered high certainty, effectively expanding the applicability of this technique to a greater proportion of patients. Conclusions: Our results demonstrate an improvement in concordance between immunohistochemistry-based and gene expression-based methods to predict breast cancer recurrence risk following two simple modifications to the conventional scoring model.
Language	English
Publishing date	2018-12-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2059861-0
ISSN	1472-6890
ISSN	1472-6890
DOI	10.1186/s12907-018-0082-3
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Article ; Online: Estimation of Fine-Scale Histologic Features at Low Magnification.

Zarella, Mark D / Quaschnick, Matthew R / Breen, David E / Garcia, Fernando U

Archives of pathology & laboratory medicine

2018 Volume 142, Issue 11, Page(s) 1394–1402

Abstract: Context.—: Whole-slide imaging has ushered in a new era of technology that has fostered the use of computational image analysis for diagnostic support and has begun to transfer the act of analyzing a slide to computer monitors. Due to the overwhelming ... ...

Abstract	Context.—: Whole-slide imaging has ushered in a new era of technology that has fostered the use of computational image analysis for diagnostic support and has begun to transfer the act of analyzing a slide to computer monitors. Due to the overwhelming amount of detail available in whole-slide images, analytic procedures-whether computational or visual-often operate at magnifications lower than the magnification at which the image was acquired. As a result, a corresponding reduction in image resolution occurs. It is unclear how much information is lost when magnification is reduced, and whether the rich color attributes of histologic slides can aid in reconstructing some of that information. Objective.—: To examine the correspondence between the color and spatial properties of whole-slide images to elucidate the impact of resolution reduction on the histologic attributes of the slide. Design.—: We simulated image resolution reduction and modeled its effect on classification of the underlying histologic structure. By harnessing measured histologic features and the intrinsic spatial relationships between histologic structures, we developed a predictive model to estimate the histologic composition of tissue in a manner that exceeds the resolution of the image. Results.—: Reduction in resolution resulted in a significant loss of the ability to accurately characterize histologic components at magnifications less than ×10. By utilizing pixel color, this ability was improved at all magnifications. Conclusions.—: Multiscale analysis of histologic images requires an adequate understanding of the limitations imposed by image resolution. Our findings suggest that some of these limitations may be overcome with computational modeling.
MeSH term(s)	Algorithms ; Breast Neoplasms/diagnosis ; Computer Simulation ; Female ; Humans ; Image Interpretation, Computer-Assisted/methods
Language	English
Publishing date	2018-06-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	194119-7
ISSN	1543-2165 ; 0363-0153 ; 0096-8528 ; 0003-9985
ISSN (online)	1543-2165
ISSN	0363-0153 ; 0096-8528 ; 0003-9985
DOI	10.5858/arpa.2017-0380-OA
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Article: Cue combination encoding via contextual modulation of V1 and V2 neurons.

Zarella, Mark D / Ts'o, Daniel Y

Eye and brain

2016 Volume 8, Page(s) 177–193

Abstract: Neurons in early visual cortical areas encode the local properties of a stimulus in a number of different feature dimensions such as color, orientation, and motion. It has been shown, however, that stimuli presented well beyond the confines of the ... ...

Abstract	Neurons in early visual cortical areas encode the local properties of a stimulus in a number of different feature dimensions such as color, orientation, and motion. It has been shown, however, that stimuli presented well beyond the confines of the classical receptive field can augment these responses in a way that emphasizes these local attributes within the greater context of the visual scene. This mechanism imparts global information to cells that are otherwise considered local feature detectors and can potentially serve as an important foundation for surface segmentation, texture representation, and figure-ground segregation. The role of early visual cortex toward these functions remains somewhat of an enigma, as it is unclear how surface segmentation cues are integrated from multiple feature dimensions. We examined the impact of orientation- and motion-defined surface segmentation cues in V1 and V2 neurons using a stimulus in which the two features are completely separable. We find that, although some cells are modulated in a cue-invariant manner, many cells are influenced by only one cue or the other. Furthermore, cells that are modulated by both cues tend to be more strongly affected when both cues are presented together than when presented individually. These results demonstrate two mechanisms by which cue combinations can enhance salience. We find that feature-specific populations are more frequently encountered in V1, while cue additivity is more prominent in V2. These results highlight how two strongly interconnected areas at different stages in the cortical hierarchy can potentially contribute to scene segmentation.
Language	English
Publishing date	2016-10-21
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2587460-3
ISSN	1179-2744
ISSN	1179-2744
DOI	10.2147/EB.S105616
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Article ; Online: An alternative reference space for H&E color normalization.

Zarella, Mark D / Yeoh, Chan / Breen, David E / Garcia, Fernando U

PloS one

2017 Volume 12, Issue 3, Page(s) e0174489

Abstract: Digital imaging of H&E stained slides has enabled the application of image processing to support pathology workflows. Potential applications include computer-aided diagnostics, advanced quantification tools, and innovative visualization platforms. ... ...

Abstract	Digital imaging of H&E stained slides has enabled the application of image processing to support pathology workflows. Potential applications include computer-aided diagnostics, advanced quantification tools, and innovative visualization platforms. However, the intrinsic variability of biological tissue and the vast differences in tissue preparation protocols often lead to significant image variability that can hamper the effectiveness of these computational tools. We developed an alternative representation for H&E images that operates within a space that is more amenable to many of these image processing tools. The algorithm to derive this representation operates by exploiting the correlation between color and the spatial properties of the biological structures present in most H&E images. In this way, images are transformed into a structure-centric space in which images are segregated into tissue structure channels. We demonstrate that this framework can be extended to achieve color normalization, effectively reducing inter-slide variability.
MeSH term(s)	Breast Neoplasms/diagnostic imaging ; Breast Neoplasms/pathology ; Coloring Agents/chemistry ; Eosine Yellowish-(YS)/chemistry ; Female ; Hematoxylin/chemistry ; Humans ; Image Processing, Computer-Assisted ; Mammary Glands, Human/diagnostic imaging ; Mammary Glands, Human/pathology ; Staining and Labeling
Chemical Substances	Coloring Agents ; Eosine Yellowish-(YS) (TDQ283MPCW) ; Hematoxylin (YKM8PY2Z55)
Language	English
Publishing date	2017-03-29
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0174489
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Article ; Online: Quantitative Image Analysis for Tissue Biomarker Use: A White Paper From the Digital Pathology Association.

Lara, Haydee / Li, Zaibo / Abels, Esther / Aeffner, Famke / Bui, Marilyn M / ElGabry, Ehab A / Kozlowski, Cleopatra / Montalto, Michael C / Parwani, Anil V / Zarella, Mark D / Bowman, Douglas / Rimm, David / Pantanowitz, Liron

Applied immunohistochemistry & molecular morphology : AIMM

2021 Volume 29, Issue 7, Page(s) 479–493

Abstract: Tissue biomarkers have been of increasing utility for scientific research, diagnosing disease, and treatment response prediction. There has been a steady shift away from qualitative assessment toward providing more quantitative scores for these ... ...

Abstract	Tissue biomarkers have been of increasing utility for scientific research, diagnosing disease, and treatment response prediction. There has been a steady shift away from qualitative assessment toward providing more quantitative scores for these biomarkers. The application of quantitative image analysis has thus become an indispensable tool for in-depth tissue biomarker interrogation in these contexts. This white paper reviews current technologies being employed for quantitative image analysis, their application and pitfalls, regulatory framework demands, and guidelines established for promoting their safe adoption in clinical practice.
MeSH term(s)	Biomarkers/metabolism ; Diagnostic Tests, Routine ; Humans ; Image Processing, Computer-Assisted
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-02-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	1473273-7
ISSN	1533-4058 ; 1062-3345 ; 1541-2016
ISSN (online)	1533-4058
ISSN	1062-3345 ; 1541-2016
DOI	10.1097/PAI.0000000000000930
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