Challenges in the Development, Deployment, and Regulation of Artificial Intelligence in Anatomic Pathology.

Significant advances in artificial intelligence (AI), deep learning, and other machine-learning approaches have been made in recent years, with applications found in almost every industry, including health care. AI is capable of completing a spectrum of mundane to complex medically oriented tasks previously performed only by boarded physicians, most recently assisting with the detection of cancers difficult to find on histopathology slides. Although computers will likely not replace pathologists any time soon, properly designed AI-based tools hold great potential for increasing workflow efficiency and diagnostic accuracy in pathology. Recent trends, such as data augmentation, crowdsourcing for generating annotated data sets, and unsupervised learning with molecular and/or clinical outcomes versus human diagnoses as a source of ground truth, are eliminating the direct role of pathologists in algorithm development. Proper integration of AI-based systems into anatomic-pathology practice will necessarily require fully digital imaging platforms, an overhaul of legacy information-technology infrastructures, modification of laboratory/pathologist workflows, appropriate reimbursement/cost-offsetting models, and ultimately, the active participation of pathologists to encourage buy-in and oversight. Regulations tailored to the nature and limitations of AI are currently in development and, when instituted, are expected to promote safe and effective use. This review addresses the challenges in AI development, deployment, and regulation to be overcome prior to its widespread adoption in anatomic pathology.

Cybersecurity and Information Assurance for the Clinical Laboratory.

BACKGROUND: Network-connected medical devices have rapidly proliferated in the wake of recent global catalysts, leaving clinical laboratories and healthcare organizations vulnerable to malicious actors seeking to ransom sensitive healthcare information. As organizations become increasingly dependent on integrated systems and data-driven patient care operations, a sudden cyberattack and the associated downtime can have a devastating impact on patient care and the institution as a whole. Cybersecurity, information security, and information assurance principles are, therefore, vital for clinical laboratories to fully prepare for what has now become inevitable, future cyberattacks. CONTENT: This review aims to provide a basic understanding of cybersecurity, information security, and information assurance principles as they relate to healthcare and the clinical laboratories. Common cybersecurity risks and threats are defined in addition to current proactive and reactive cybersecurity controls. Information assurance strategies are reviewed, including traditional castle-and-moat and zero-trust security models. Finally, ways in which clinical laboratories can prepare for an eventual cyberattack with extended downtime are discussed. SUMMARY: The future of healthcare is intimately tied to technology, interoperability, and data to deliver the highest quality of patient care. Understanding cybersecurity and information assurance is just the first preparative step for clinical laboratories as they ensure the protection of patient data and the continuity of their operations.

Organizational preparedness for the use of large language models in pathology informatics.

In this paper, we consider the current and potential role of the latest generation of Large Language Models (LLMs) in medical informatics, particularly within the realms of clinical and anatomic pathology. We aim to provide a thorough understanding of the considerations that arise when employing LLMs in healthcare settings, such as determining appropriate use cases and evaluating the advantages and limitations of these models. Furthermore, this paper will consider the infrastructural and organizational requirements necessary for the successful implementation and utilization of LLMs in healthcare environments. We will discuss the importance of addressing education, security, bias, and privacy concerns associated with LLMs in clinical informatics, as well as the need for a robust framework to overcome regulatory, compliance, and legal challenges.

Artificial intelligence and digital pathology: clinical promise and deployment considerations.

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.

Computational pathology in 2030: a Delphi study forecasting the role of AI in pathology within the next decade.

BACKGROUND: Artificial intelligence (AI) is rapidly fuelling a fundamental transformation in the practice of pathology. However, clinical integration remains challenging, with no AI algorithms to date in routine adoption within typical anatomic pathology (AP) laboratories. This survey gathered current expert perspectives and expectations regarding the role of AI in AP from those with first-hand computational pathology and AI experience. METHODS: Perspectives were solicited using the Delphi method from 24 subject matter experts between December 2020 and February 2021 regarding the anticipated role of AI in pathology by the year 2030. The study consisted of three consecutive rounds: 1) an open-ended, free response questionnaire generating a list of survey items; 2) a Likert-scale survey scored by experts and analysed for consensus; and 3) a repeat survey of items not reaching consensus to obtain further expert consensus. FINDINGS: Consensus opinions were reached on 141 of 180 survey items (78.3%). Experts agreed that AI would be routinely and impactfully used within AP laboratory and pathologist clinical workflows by 2030. High consensus was reached on 100 items across nine categories encompassing the impact of AI on (1) pathology key performance indicators (KPIs) and (2) the pathology workforce and specific tasks performed by (3) pathologists and (4) AP lab technicians, as well as (5) specific AI applications and their likelihood of routine use by 2030, (6) AI's role in integrated diagnostics, (7) pathology tasks likely to be fully automated using AI, and (8) regulatory/legal and (9) ethical aspects of AI integration in pathology. INTERPRETATION: This systematic consensus study details the expected short-to-mid-term impact of AI on pathology practice. These findings provide timely and relevant information regarding future care delivery in pathology and raise key practical, ethical, and legal challenges that must be addressed prior to AI's successful clinical implementation. FUNDING: No specific funding was provided for this study.

Quantitative Image Analysis as an Adjunct to Manual Scoring of ER, PgR, and HER2 in Invasive Breast Carcinoma.

OBJECTIVES: Biomarker expression evaluation for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) is an essential prognostic and predictive parameter for breast cancer and critical for guiding hormonal and neoadjuvant therapy. This study compared quantitative image analysis (QIA) with pathologists' scoring for ER, PgR, and HER2. METHODS: A retrospective analysis was undertaken of 1,367 invasive breast carcinomas, including all histopathology subtypes, for which ER, PgR, and HER2 were analyzed by manual scoring and QIA. The resulting scores were compared, and in a subset of HER2 cases (n = 373, 26%), scores were correlated with available fluorescence in situ hybridization (FISH) results. RESULTS: Concordance between QIA and manual scores for ER, PgR, and HER2 was 93%, 96%, and 90%, respectively. Discordant cases had low positive scores (1%-10%) for ER (n = 33), were due to nonrepresentative region selection (eg, ductal carcinoma in situ) or tumor heterogeneity for PgR (n = 43), and were of one-step difference (negative to equivocal, equivocal to positive, or vice versa) for HER2 (n = 90). Among HER2 cases where FISH results were available, only four (1.0%) showed discordant QIA and FISH results. CONCLUSIONS: QIA is a computer-aided diagnostic support tool for pathologists. It significantly improves ER, PgR, and HER2 scoring standardization. QIA demonstrated excellent concordance with pathologists' scores. To avoid pitfalls, pathologist oversight of representative region selection is recommended.

Contemporary Whole Slide Imaging Devices and Their Applications within the Modern Pathology Department: A Selected Hardware Review.

Digital pathology (DP) has disrupted the practice of traditional pathology, including applications in education, research, and clinical practice. Contemporary whole slide imaging (WSI) devices include technological advances that help address some of the challenges facing modern pathology, such as increasing workloads with fewer subspecialized pathologists, expanding integrated delivery networks with global reach, and greater customization when working up cases for precision medicine. This review focuses on integral hardware components of 43 market available and soon-to-be released digital WSI devices utilized throughout the world. Components such as objective lens type and magnification, scanning camera, illumination, and slide capacity were evaluated with respect to scan time, throughput, accuracy of scanning, and image quality. This analysis of assorted modern WSI devices offers essential, valuable information for successfully selecting and implementing a digital WSI solution for any given pathology practice.

Display Characteristics and Their Impact on Digital Pathology: A Current Review of Pathologists' Future "Microscope".

Digital displays (monitors) are an indispensable component of a pathologists' daily workflow, from writing reports, viewing whole-slide images, or browsing the Internet. Due to a paucity of literature and experience surrounding display use and standardization in pathology, the Food and Drug Administration's (FDA) has currently restricted FDA-cleared whole-slide imaging systems to a specific model of display for each system, which at this time consists of only medical-grade (MG) displays. Further, given that a pathologists' display will essentially become their new surrogate "microscope," it becomes exceedingly important that all pathologists have a basic understanding of fundamental display properties and their functional consequences. This review seeks to: (a) define and summarize the current and emerging display technology, terminology, features, and regulation as they pertain to pathologists and review the current literature on the impact of different display types (e.g. MG vs. consumer off the shelf vs. professional grade) on pathologists' diagnostic performance and (b) discuss the impact of the recent digital pathology device componentization and the coronavirus disease 2019 public emergency on the pixel pathway and display use for remote digital pathology. Display technology has changed dramatically over the past 20 years and continues to change at a rapid rate. There is a paucity of published studies to date that investigate how display type affects pathologist performance, with more research necessary in order to develop standards and minimum specifications for displays in digital pathology. Given the complexity of modern displays, pathologists must become better informed regarding display technology if they wish to have more choice over their future "microscopes."

Bcl-2 family members and functional electron transport chain regulate oxygen deprivation-induced cell death.

The mechanisms underlying cell death during oxygen deprivation are unknown. We report here a model for oxygen deprivation-induced apoptosis. The death observed during oxygen deprivation involves a decrease in the mitochondrial membrane potential, followed by the release of cytochrome c and the activation of caspase-9. Bcl-X(L) prevented oxygen deprivation-induced cell death by inhibiting the release of cytochrome c and caspase-9 activation. The ability of Bcl-X(L) to prevent cell death was dependent on allowing the import of glycolytic ATP into the mitochondria to generate an inner mitochondrial membrane potential through the F(1)F(0)-ATP synthase. In contrast, although activated Akt has been shown to inhibit apoptosis induced by a variety of apoptotic stimuli, it did not prevent cell death during oxygen deprivation. In addition to Bcl-X(L), cells devoid of mitochondrial DNA (rho degrees cells) that lack a functional electron transport chain were resistant to oxygen deprivation. Further, murine embryonic fibroblasts from bax(-/-) bak(-/-) mice did not die in response to oxygen deprivation. These data suggest that when subjected to oxygen deprivation, cells die as a result of an inability to maintain a mitochondrial membrane potential through the import of glycolytic ATP. Proapoptotic Bcl-2 family members and a functional electron transport chain are required to initiate cell death in response to oxygen deprivation.

Pathology informatics fellowship training: Focus on molecular pathology.

BACKGROUND: Pathology informatics is both emerging as a distinct subspecialty and simultaneously becoming deeply integrated within the breadth of pathology practice. As specialists, pathology informaticians need a broad skill set, including aptitude with information fundamentals, information systems, workflow and process, and governance and management. Currently, many of those seeking training in pathology informatics additionally choose training in a second subspecialty. Combining pathology informatics training with molecular pathology is a natural extension, as molecular pathology is a subspecialty with high potential for application of modern biomedical informatics techniques. METHODS AND RESULTS: Pathology informatics and molecular pathology fellows and faculty evaluated the current fellowship program's core curriculum topics and subtopics for relevance to molecular pathology. By focusing on the overlap between the two disciplines, a structured curriculum consisting of didactics, operational rotations, and research projects was developed for those fellows interested in both pathology informatics and molecular pathology. CONCLUSIONS: The scope of molecular diagnostics is expanding dramatically as technology advances and our understanding of disease extends to the genetic level. Here, we highlight many of the informatics challenges facing molecular pathology today, and outline specific informatics principles necessary for the training of future molecular pathologists.

The ongoing evolution of the core curriculum of a clinical fellowship in pathology informatics.

The Partners HealthCare system's Clinical Fellowship in Pathology Informatics (Boston, MA, USA) faces ongoing challenges to the delivery of its core curriculum in the forms of: (1) New classes of fellows annually with new and varying educational needs and increasingly fractured, enterprise-wide commitments; (2) taxing electronic health record (EHR) and laboratory information system (LIS) implementations; and (3) increasing interest in the subspecialty at the academic medical centers (AMCs) in what is a large health care network. In response to these challenges, the fellowship has modified its existing didactic sessions and piloted both a network-wide pathology informatics lecture series and regular "learning laboratories". Didactic sessions, which had previously included more formal discussions of the four divisions of the core curriculum: Information fundamentals, information systems, workflow and process, and governance and management, now focus on group discussions concerning the fellows' ongoing projects, updates on the enterprise-wide EHR and LIS implementations, and directed questions about weekly readings. Lectures are given by the informatics faculty, guest informatics faculty, current and former fellows, and information systems members in the network, and are open to all professional members of the pathology departments at the AMCs. Learning laboratories consist of small-group exercises geared toward a variety of learning styles, and are driven by both the fellows and a member of the informatics faculty. The learning laboratories have created a forum for discussing real-time and real-world pathology informatics matters, and for incorporating awareness of and timely discussions about the latest pathology informatics literature. These changes have diversified the delivery of the fellowship's core curriculum, increased exposure of faculty, fellows and trainees to one another, and more equitably distributed teaching responsibilities among the entirety of the pathology informatics asset in the network. Though the above approach has been in place less than a year, we are presenting it now as a technical note to allow for further discussion of evolving educational opportunities in pathology informatics and clinical informatics in general, and to highlight the importance of having a flexible fellowship with active participation from its fellows.

Using computerized workflow simulations to assess the feasibility of whole slide imaging full adoption in a high-volume histology laboratory.

BACKGROUND: Whole slide Imaging (WSI) has been touted by many as the future of pathology, with estimates of full adoption occurring sometime in the next 5 to 15 years. While WSI devices have become increasingly capable since their inception, there has been little consideration of how WSI will be implemented and subsequently affect the workflow of high volume histology laboratories. METHODS: Histology workflow process data was collected from a high-volume histology laboratory (Massachusetts General Hospital) and a process model developed using business process management software. Computerized workflow simulations were performed and total histology process time evaluated under a number of different WSI conditions. RESULTS: Total histology process time increased approximately 10-fold to 20-fold over baseline with the presence of one WSI robot in the histology workflow. Depending on the specifications of the WSI robot, anywhere from 9 to 14 WSI robots were required within the histology workflow to minimize the effects of WSI. CONCLUSIONS: Placing a WSI robot into the current workflow of a high-volume histology laboratory with the intent of full adoption is not feasible. Implementing WSI without making significant changes to the current workflow of the histology laboratory would prove to be both disruptive and costly to surgical pathology.

Clinical fellowship training in pathology informatics: A program description.

BACKGROUND: In 2007, our healthcare system established a clinical fellowship program in pathology informatics. In 2011, the program benchmarked its structure and operations against a 2009 white paper "Program requirements for fellowship education in the subspecialty of clinical informatics", endorsed by the Board of the American Medical Informatics Association (AMIA) that described a proposal for a general clinical informatics fellowship program. METHODS: A group of program faculty members and fellows compared each of the proposed requirements in the white paper with the fellowship program's written charter and operations. The majority of white paper proposals aligned closely with the rules and activities in our program and comparison was straightforward. In some proposals, however, differences in terminology, approach, and philosophy made comparison less direct, and in those cases, the thinking of the group was recorded. After the initial evaluation, the remainder of the faculty reviewed the results and any disagreements were resolved. RESULTS: The most important finding of the study was how closely the white paper proposals for a general clinical informatics fellowship program aligned with the reality of our existing pathology informatics fellowship. The program charter and operations of the program were judged to be concordant with the great majority of specific white paper proposals. However, there were some areas of discrepancy and the reasons for the discrepancies are discussed in the manuscript. CONCLUSIONS: After the comparison, we conclude that the existing pathology informatics fellowship could easily meet all substantive proposals put forth in the 2009 clinical informatics program requirements white paper. There was also agreement on a number of philosophical issues, such as the advantages of multiple fellows, the need for core knowledge and skill sets, and the need to maintain clinical skills during informatics training. However, there were other issues, such as a requirement for a 2-year fellowship and for informatics fellowships to be done after primary board certification, that pathology should consider carefully as it moves toward a subspecialty status and board certification.

Different tracks for pathology informatics fellowship training: Experiences of and input from trainees in a large multisite fellowship program.

BACKGROUND: Pathology Informatics is a new field; a field that is still defining itself even as it begins the formalization, accreditation, and board certification process. At the same time, Pathology itself is changing in a variety of ways that impact informatics, including subspecialization and an increased use of data analysis. In this paper, we examine how these changes impact both the structure of Pathology Informatics fellowship programs and the fellows' goals within those programs. MATERIALS AND METHODS: As part of our regular program review process, the fellows evaluated the value and effectiveness of our existing fellowship tracks (Research Informatics, Clinical Two-year Focused Informatics, Clinical One-year Focused Informatics, and Clinical 1 + 1 Subspecialty Pathology and Informatics). They compared their education, informatics background, and anticipated career paths and analyzed them for correlations between those parameters and the fellowship track chosen. All current and past fellows of the program were actively involved with the project. RESULTS: Fellows' anticipated career paths correlated very well with the specific tracks in the program. A small set of fellows (Clinical - one or two year - Focused Informatics tracks) anticipated clinical careers primarily focused in informatics (Director of Informatics). The majority of the fellows, however, anticipated a career practicing in a Pathology subspecialty, using their informatics training to enhance that practice (Clinical 1 + 1 Subspecialty Pathology and Informatics Track). Significantly, all fellows on this track reported they would not have considered a Clinical Two-year Focused Informatics track if it was the only track offered. The Research and the Clinical One-year Focused Informatics tracks each displayed unique value for different situations. CONCLUSIONS: It seems a "one size fits all" fellowship structure does not fit the needs of the majority of potential Pathology Informatics candidates. Increasingly, these fellowships must be able to accommodate the needs of candidates anticipating a wide range of Pathology Informatics career paths, be able to accommodate Pathology's increasingly subspecialized structure, and do this in a way that respects the multiple fellowships needed to become a subspecialty pathologist and informatician. This is further complicated as Pathology Informatics begins to look outward and takes its place in the growing, and still ill-defined, field of Clinical Informatics, a field that is not confined to just one medical specialty, to one way of practicing medicine, or to one way of providing patient care.