In the two decades since Accreditation Council for Graduate Medical Education (ACGME)–accredited Molecular Genetic Pathology (MGP) fellowships have existed and the American Board of Pathology (ABPath) has been offering a certification examination in partnership with the American Board of Medical Genetics and Genomics, the field of clinical molecular pathology has evolved considerably. Clinical applications have expanded significantly, and available technologies have advanced through several iterations, dramatically improving molecular pathologists' analytic capabilities. Although the curricula covered during MGP fellowships have also evolved, there has been no study to date examining what skills and knowledge current MGP practitioners actually require for their jobs. Thus, the ABPath undertook a survey of MGP diplomates participating in continuing certification (formerly maintenance of certification) to assess the alignment of practice needs and training content (referred to herein as the ABPath survey). The data were shared with an ad hoc committee of molecular pathology colleagues, the Molecular Genetic Pathology Curriculum UPdate working group, sponsored by the Association for Molecular Pathology (AMP). This group developed a parallel survey of the MGP fellowship program directors (PDs; referred to as the AMP PD survey). The two sets of data provide a detailed look at the needs, perceptions, and evolution of MGP education. The ABPath survey asked diplomates to reflect on the training they received several years earlier, and how well it prepared them for their current jobs, whereas the AMP PD survey looked at current training that prepares MGP fellows broadly, for certification and for a variety of jobs.

DiscussionPublications recommending specific curricula for molecular genetic pathology and genomics training have tended to focus on pathology residents, non-MGP pathology fellows, or practicing pathologists.2Schrijver I. Natkunam Y. Galli S. Boyd S.D. Integration of genomic medicine into pathology residency training: the Stanford open curriculum., 3Haspel R.L. Ali A.M. Huang G.C. Smith M.H. Atkinson J.B. Chabot-Richards D.S. Elliott R.M. Kaul K.L. Powell S.Z. Rao A. Rinder H.M. Vanderbilt C.M. Wilcox R. Teaching genomic pathology: translating team-based learning to a virtual environment using computer-based simulation., 4Aisner D.L. Berry A. Dawson D.B. Hayden R.T. Joseph L. Hill C.E. A suggested molecular pathology curriculum for residents: a report of the Association for Molecular Pathology., 5Laudadio J. McNeal J.L. Boyd S.D. Le L.P. Lockwood C. McCloskey C.B. Sharma G. Voelkerding K.V. Haspel R.L. Design of a genomics curriculum: competencies for practicing pathologists., 6Beck R.C. Kim A.S. Goswami R.S. Weinberg O.K. Yeung C.C.S. Ewalt M.D. Molecular/cytogenetic education for hematopathology fellows. As specialists in molecular pathology, MGP fellows should be expected to achieve mastery of all topics covered in residency programs in addition to deeper understanding than that of a typical pathology resident. More than a decade ago, Talbert et al7Talbert M.L. Dunn S.T. Hunt J. Hillyard D.R. Mirza I. Nowak J.A. Van Deerlin V. Vnencak-Jones C.L. Competency-based education for the molecular genetic pathology fellow: a report of the Association for Molecular Pathology Training and Education Committee. published a competency-based education for MGP fellows using the six ACGME core competencies. They presented learning goals and assessment tools for each competency: patient care, medical knowledge, systems-based practice, problem-based learning and improvement, professionalism, and interpersonal communication and skills. Molecular genetic pathology ACGME milestones version 1 followed in 2014 and version 2 in 2021, offering core competency-based guideposts that could serve as curricular goals for training (Accreditation Council for Graduate Medical Education, Molecular Genetic Pathology Milestones, 2021, https://www.acgme.org/globalassets/pdfs/milestones/moleculargeneticpathologymilestones.pdf, last accessed January 4, 2021). However, an updated, analytical review of the more recent and current practice of MGP diplomates, and the perceived requirements from the program directors that lead MGP training programs, is warranted to ensure that molecularly based clinical care is up-to-date and relevant. Examples of topics requiring increased emphasis within each area of training focus (informatics, bioinformatics, solid tumor testing, hematopathology, constitutional genetics, infectious disease, laboratory management, and professional development) are provided in Table 1 and reflect the expert opinion of the authors, based on changes in the practice in molecular pathology and the findings in these surveys.

The survey data suggested that some topics can be critically important to the practice of a subset of MGP diplomates yet unimportant to another. Although some foundational topics, such as molecular genetic principles, PCR, Sanger sequencing, and, increasingly, NGS, were generally accepted to be core knowledge, other areas, such as inherited disease and germline NGS testing, molecular virology, microsatellite instability, and bone marrow engraftment, were examples of subject areas with high variability in perceived importance. Overall, despite the relative lack of literature on specifics for MGP training in basic principles and technical topics, programs have tailored their efforts to the perceived needs. Programs must train for the breadth of the field, although some diplomates will not utilize all areas of their training once they enter the job market.

Concomitant with the increase in reliance on high-complexity technology, it has become imperative that molecular pathologists have at least baseline knowledge in informatics and bioinformatics to effectively communicate with computational teams during assay validation, result interpretation, and reporting. Former fellows and PDs agree these topics are an important component of training. Most programs include informatics and bioinformatics education in the curricula, although many diplomates felt the need for more extensive training, and many programs lack a bioinformaticist on faculty. Although informatics may be covered more formally in the residency setting, bioinformatics is especially crucial and specific to the practice of molecular diagnostics, and several guidelines and recommendations have been published for cancer testing,8Li M.M. Datto M. Duncavage E.J. Kulkarni S. Lindeman N.I. Roy S. Tsimberidou A.M. Vnencak-Jones C.L. Wolff D.J. Younes A. Nikiforova M.N. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. germline disorders,9Richards S. Aziz N. Bale S. Bick D. Das S. Gastier-Foster J. Grody W.W. Hegde M. Lyon E. Spector E. Voelkerding K. Rehm H.L. ACMG Laboratory Quality Assurance Committee
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. and validation of NGS pipelines.10Roy S. Coldren C. Karunamurthy A. Kip N.S. Klee E.W. Lincoln S.E. Leon A. Pullambhatla M. Temple-Smolkin R.L. Voelkerding K.V. Wang C. Carter A.B. Standards and guidelines for validating next-generation sequencing bioinformatics pipelines: a joint recommendation of the Association for Molecular Pathology and the College of American Pathologists. Relevant informatics topics include databases, laboratory information systems, and ordering and reporting workflows, and critical bioinformatics topics include bioinformatics pipelines, with a focus on understanding the nuances of variant calling, annotation, and interpretation as well as computationally derived biomarkers.

The molecular oncology of solid tumors and hematologic malignancies has emerged as one of the fastest growing subdisciplines in molecular pathology. The two surveys provided largely consistent results regarding training for molecular testing in oncology, including the critical need to teach and learn details of sequencing and amplification technologies. The AMP PD survey allowed more granularity in terms of investigating the investment into different amplification approaches, with those findings broadly reflecting the impact of those approaches on laboratory medicine at that time. Some differences emerged for technologies, such as Sanger sequencing, with PDs continuing to place emphasis on this technology, whereas learners tended to downgrade its importance, likely reflecting the current emphasis on higher-throughput technologies, such as NGS. Finally, although there was broad agreement in the traditionally molecular areas, there seemed to be diminishing enthusiasm for conventional cytogenetic technologies, including microarray, FISH, and karyotyping. Especially for microarrays, survey data supported the idea that the diminished enthusiasm was directed more at constitutional cytogenetics, and might not reflect opinions on these technologies as they pertain to the somatic setting. Although this decline was noted by both PDs and learners, it was more pronounced in the ABPath results, suggesting that learners are not as aware of the continuing need for some conventional approaches in molecular pathology as their own practice had become highly specialized.

Although not specifically addressed in either survey, it is important to note the need for training in pre-analytic and postanalytic variables. Variables, such as biopsy size, adequate tumor cellularity, and potential artifacts, introduced by fixation techniques that could potentially affect results need to be included not only in training of AP residents but firmly mastered during the MGP curriculum.11Compton C.C. Robb J.A. Anderson M.W. Berry A.B. Birdsong G.G. Bloom K.J. Branton P.A. Crothers J.W. Cushman-Vokoun A.M. Hicks D.G. Khoury J.D. Laser J. Marshall C.B. Misialek M.J. Natale K.E. Nowak J.A. Olson D. Pfeifer J.D. Schade A. Vance G.H. Walk E.E. Yohe S.L. Preanalytics and precision pathology: pathology practices to ensure molecular integrity of cancer patient biospecimens for precision medicine.,12Arreaza G. Qiu P. Pang L. Albright A. Hong L.Z. Marton M.J. Levitan D. Pre-analytical considerations for successful next-generation sequencing (NGS): challenges and opportunities for formalin-fixed and paraffin-embedded tumor tissue (FFPE) samples. Fellows lacking a background in anatomic pathology may find some of these principles more challenging. Additional considerations for analyses of hematologic malignancies include the fact that a greater variety of sample types are accepted for testing, including fresh or frozen peripheral blood or bone marrow, further impacting the performance and interpretation of molecular investigations. In hematologic disorders, or cell-free DNA testing of solid tumors, the risk of misinterpreting variants stemming from clonal hematopoiesis of indeterminate potential is also present.13Clinical consequences of clonal hematopoiesis of indeterminate potential.,14Liu J. Chen X. Wang J. Zhou S. Wang C.L. Ye M.Z. Wang X.Y. Song Y. Wang Y.Q. Zhang L.T. Wu R.H. Yang H.M. Zhu S.D. Zhou M.Z. Zhang X.C. Zhu H.M. Qian Z.Y. Biological background of the genomic variations of cf-DNA in healthy individuals. It is also important that MGP fellows training in solid tumors/hematopathology have an in-depth understanding of the importance of germline mutation testing and analysis, including ethical and consent issues, given that germline mutations could be identified in the setting of somatic mutation analysis.15Cushman-Vokoun A. Lauring J. Pfeifer J. Olson D.R. Berry A. Thorson J. Voelkerding K. Myles J. Barbeau J. Chandra P. Li M. Vance G.H. Jensen B.W. Hansen M.Y. Yohe S. Laboratory and clinical implications of incidental and secondary germline findings during tumor testing. Finally, MGP fellows should have an adequate understanding of pathologic disease processes and differential diagnoses of a certain cancer, and how these may relate to a specific tumor profile. MGP fellows should also understand the limitations of molecular testing and that, in certain contexts, a molecular and cytogenetic profile may only aid in diagnosis, in conjunction with clinical and histopathologic data.

The field of constitutional genetic testing also continues to evolve rapidly, largely due to the increasing implementation of large gene panels or exomes to diagnose disease, as well as increased cataloging of genes that may alter risk for hereditary syndromes. Although results indicate a perception of lower importance of noncancer genetic testing among MGP diplomates and PDs, perhaps because most constitutional genetics testing is done by American Board of Medical Genetics and Genomics–trained professionals, understanding the range and resolution of technologies that can be applied to the study of constitutional disorders, from karyotyping, FISH, microarray, targeted molecular analysis, and NGS, is critical for all MGP fellows. A thorough working knowledge of the platforms and variant types that can or cannot be detected with each is essential to ensure accuracy in reporting and optimal guidance for treating physicians. Constitutional genetic testing requires a solid foundational knowledge of the structure of the human genome and its normal variation, mendelian and nonmendelian patterns of inheritance, and common mechanisms of mutation. At the clinical level, clear understanding of the difference between screening and diagnostic testing, the limitations and quality metrics of various platforms, as well as norms for reporting are critical. Germline testing also comes with challenges, some of which are unique to the constitutional setting, including ethical considerations stemming from the familial nature of testing information, as well as the appropriate identification and interpretation of mosaicism.

Molecular microbiology is another foundational subject in molecular genetic pathology. Molecular methods have been a mainstay in infectious disease diagnostics since the 1980s, starting with the molecular detection of viruses, which were slow to culture and difficult to visually identify. Today, most hospital laboratories use nucleic acid testing for detection and quantification of many microorganisms and select antimicrobial resistance markers. Understanding these assays is important for all pathologists, especially molecular pathologists. However, as the molecular diagnostics field has grown and technology has advanced, subspecialization has occurred and not all molecular pathologists are currently involved in molecular microbiology. We speculate that increased adoption of molecular methods, particularly US Food and Drug Administration–approved sample to answer syndromic test panels (eg, respiratory viral panels and gastrointestinal pathogen panels) performed on automated instruments may underlie the desire for de-emphasis of infectious disease testing in the highly specialized training curriculum.16Murphy C.N. Fowler R. Balada-Llasat J.M. Carroll A. Stone H. Akerele O. Buchan B. Windham S. Hopp A. Ronen S. Relich R.F. Buckner R. Warren D.A. Humphries R. Campeau S. Huse H. Chandrasekaran S. Leber A. Everhart K. Harrington A. Kwong C. Bonwit A. Dien Bard J. Naccache S. Zimmerman C. Jones B. Rindlisbacher C. Buccambuso M. Clark A. Rogatcheva M. Graue C. Bourzac K.M. Multicenter evaluation of the BioFire FilmArray pneumonia/pneumonia plus panel for detection and quantification of agents of lower respiratory tract infection., 17Ramanan P. Bryson A.L. Binnicker M.J. Pritt B.S. Patel R. Syndromic panel-based testing in clinical microbiology., 18Leber A.L. Everhart K. Balada-Llasat J.-M. Cullison J. Daly J. Holt S. Lephart P. Salimnia H. Schreckenberger P.C. DesJarlais S. Reed S.L. Chapin K.C. LeBlanc L. Johnson J.K. Soliven N.L. Carroll K.C. Miller J.-A. Dien Bard J. Mestas J. Bankowski M. Enomoto T. Hemmert A.C. Bourzac K.M. Multicenter evaluation of BioFire FilmArray meningitis/encephalitis panel for detection of bacteria, viruses, and yeast in cerebrospinal fluid specimens. Possibly leading to a further perceived unimportance by trainees and program directors, these panel-based tests are often performed in the microbiology laboratory,19Dien Bard J. McElvania E. Panels and syndromic testing in clinical microbiology. directed by clinical pathologists with subspeciality training or nonphysician scientists credentialed through the American Board of Medical Microbiology. Despite such variation in the professional world, both molecular pathologists and clinical microbiologists should be familiar with verification of a US Food and Drug Administration–approved molecular assay and validation of a laboratory-developed molecular assay, be well versed in troubleshooting assays, such as sample issues and discrepant results, and be prepared for new challenges, such as antimicrobial stewardship.20Buchan B.W. Windham S. Balada-Llasat J.-M. Leber A. Harrington A. Relich R. Murphy C. Dien Bard J. Naccache S. Ronen S. Hopp A. Mahmutoglu D. Faron M.L. Ledeboer N.A. Carroll A. Stone H. Akerele O. Everhart K. Bonwit A. Kwong C. Buckner R. Warren D. Fowler R. Chandrasekaran S. Huse H. Campeau S. Humphries R. Graue C. Huang A. Practical comparison of the BioFire FilmArray pneumonia panel to routine diagnostic methods and potential impact on antimicrobial stewardship in adult hospitalized patients with lower respiratory tract infections., 21Validation of laboratory-developed molecular assays for infectious diseases., 22Halling K.C. Schrijver I. Persons D.L. Test verification and validation for molecular diagnostic assays.More complex techniques, such as NGS in infectious disease testing, are not yet commonly used in the clinical setting. Despite the fact that NGS testing can be used to identify microbes directly from a sample without need for culture, can characterize polymicrobial populations, can detect genetic virulence factors or drug-resistance mutations, and can manage pathogen outbreaks,23Olsen R.J. Fittipaldi N. Kachroo P. Sanson M.A. Long S.W. Como-Sabetti K.J. Valson C. Cantu C. Lynfield R. Van Beneden C. Beres S.B. Musser J.M. Clinical laboratory response to a mock outbreak of invasive bacterial infections: a preparedness study., 24Lefterova M.I. Suarez C.J. Banaei N. Pinsky B.A. Next-generation sequencing for infectious disease diagnosis and management: a report of the Association for Molecular Pathology., 25Rossen J.W.A. Friedrich A.W. Moran-Gilad J. ESCMID Study Group for Genomic and Molecular Diagnostics (ESGMD)
Practical issues in implementing whole-genome-sequencing in routine diagnostic microbiology., 26Ihekweazu F.D. Versalovic J. Development of the pediatric gut microbiome: impact on health and disease. it is not routinely used in most molecular diagnostic laboratories. A major obstacle is the need for specialized infrastructure, expertise, and informatics.27Long S.W. Williams D. Valson C. Cantu C.C. Cernoch P. Musser J.M. Olsen R.J. A genomic day in the life of a clinical microbiology laboratory. Future clinical applications may warrant increased emphasis of NGS and microbiome analysis in both MGP and medical microbiology training programs.28The human intestinal microbiome in health and disease.Of note, the ABPath survey was distributed before the COVID-19 pandemic, whereas the AMP PD survey was administered during the summer of 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing has obviously impacted both molecular and microbiology laboratories in an unprecedented manner, and therefore, could contribute to some discrepant findings bearing on infectious diseases between the two surveys. PDs and fellows may have increased interest in pathogen assay development and validation, public health and epidemiology, and regulatory matters,29One year later: what have we learned from COVID-19? lessons and accomplishments in academic pathology departments. as well as sequencing to characterize microbial variants.30Olsen R.J. Christensen P.A. Long S.W. Subedi S. Hodjat P. Olson R. Nguyen M. Davis J.J. Yerramilli P. Saavedra M.O. Pruitt L. Reppond K. Shyer M.N. Cambric J. Gadd R. Thakur R.M. Batajoo A. Finkelstein I.J. Gollihar J. Musser J.M. Trajectory of growth of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in Houston, Texas, January through May 2021, based on 12,476 genome sequences. One PD suggested that regulatory and public health issues need to be emphasized, including emergency use authorization and US Food and Drug Administration regulations, an insightful comment on an issue that has become critical during the COVID-19 pandemic.Laboratory management is an area that also requires well-rounded training for MGP fellowship and ideally would take place in an experience-based setting throughout the year, with supplemental modules. Several important resources exist that can facilitate the coverage of management topics important to the practice of molecular genetic pathology. The Association for Molecular Pathology has launched a comprehensive online curriculum available at no charge to members that covers a wide range of management topics in an interactive manner (eg, AMP Certificate Program: Molecular Laboratory Management and Reporting: A Short Course for Laboratory Professionals, https://www.amp.org/education/amp-courses-and-series, last accessed March 25, 2022). Several published articles address important topics related to laboratory management and finance that are suitable for resident and MGP fellow training.4Aisner D.L. Berry A. Dawson D.B. Hayden R.T. Joseph L. Hill C.E. A suggested molecular pathology curriculum for residents: a report of the Association for Molecular Pathology.,7Talbert M.L. Dunn S.T. Hunt J. Hillyard D.R. Mirza I. Nowak J.A. Van Deerlin V. Vnencak-Jones C.L. Competency-based education for the molecular genetic pathology fellow: a report of the Association for Molecular Pathology Training and Education Committee.,31Weiss R.L. Hassell L.A. Parks E.R. Progress toward improved leadership and management training in pathology. As future medical directors, MGP fellows should also be familiar with the topics covered in training for the technical staff within an MGP laboratory.32Taylor S. Bennett K.M. Deignan J.L. Hendrix E.C. Orton S.M. Verma S. Schutzbank T.E. Molecular pathology curriculum for medical laboratory scientists: a report of the Association for Molecular Pathology Training and Education Committee.,33Genetics and molecular diagnostics in the clinical laboratory science curriculum. Incorporation of scenarios for discussion of more challenging issues, such as personnel management, ethical issues, and privacy and legal topics, is recommended for teaching these concepts to MGP fellows.Professional development is a key component to graduate medical education and includes numerous educational goals, as shown in Table 1. Although most PDs indicate using a hands-on practical approach, how to successfully teach professionalism is less well defined than educational goals. Use of case-based discussions as a mechanism to teach professionalism and the recognition of unprofessional behavior can be a successful approach.34Domen R.E. Johnson K. Conran R.M. Hoffman R.D. Post M.D. Steinberg J.J. Brissette M.D. Gratzinger D.A. McCloskey C.B. Raciti P.M. Roberts C.A. Rojiani A.M. Powell S.Z. Professionalism in pathology: a case-based approach as a potential educational tool. In practice, faculty members also teach professionalism through mentoring, providing feedback as situations arise, and role modeling professional (or unprofessional) behavior.35Brissette M.D. Johnson K.A. Raciti P.M. McCloskey C.B. Gratzinger D.A. Conran R.M. Domen R.E. Hoffman R.D. Post M.D. Roberts C.A. Rojiani A.M. Powell S.Z.-E. Perceptions of unprofessional attitudes and behaviors: implications for faculty role modeling and teaching professionalism during pathology residency. On the basis of survey results, current efforts for teaching professionalism as a component of molecular genetic pathology training should continue. The incorporation of case scenarios illustrating professionalism and educating faculty on their role in teaching by example are strategies that could enhance a program's curriculum.As discussed, training in most areas aligns with the practice needs of former trainees. Prenatal FISH, infectious disease molecular testing, and some conventional techniques may not be important to the current practice of most former trainees, but practice settings differ, and PDs still view these topics as important to provide foundational knowledge. Parentage testing, identity testing, microbiome analysis, and HLA are less important topics to both survey audiences, and there may be an opportunity to reduce the emphasis of these topics in the curricula. Topic areas covered in some programs but not specifically included in the AMP PD survey included biobanking, appropriate test utilization, and teaching skills. There are many emerging areas that will require further additions to molecular genetic pathology training in the future. Liquid biopsy in patients with solid tumor malignancy is already clinically utilized, and training should be available to fellows in the nuances of this type of testing and its validation. Whole exome sequencing and whole genome sequencing, RNA sequencing, and single-cell sequencing in solid tumors will be important additions to MGP training. In addition, proteomics, pharmacogenetics, and high-throughput epigenetic analysis should be considered as potential areas for inclusion in curricula. In vitro manipulation of cells using the introduction of transgenes (eg, chimeric antigen receptor T-cell therapy) or gene editing technology (eg, CRISPR/Cas-9) may require molecular monitoring, necessitating training in these areas as well.36Cushman-Vokoun A.M. Voelkerding K.V. Fung M.K. Nowak J.A. Thorson J.A. Duncan H.L. Kalicanin T. Anderson M.W. Yohe S. A primer on chimeric antigen receptor T-cell therapy: what does it mean for pathologists?. Mutations within cellular networks as they affect cancer cell dependency37Tsherniak A. Vazquez F. Montgomery P.G. Weir B.A. Kryukov G. Cowley G.S. Gill S. Harrington W.F. Pantel S. Krill-Burger J.M. Meyers R.M. Ali L. Goodale A. Lee Y. Jiang G. Hsiao J. Gerath W.F.J. Howell S. Merkel E. Ghandi M. Garraway L.A. Root D.E. Golub T.R. Boehm J.S. Hahn W.C. Defining a cancer dependency map. and modeling tumor mutational profiles during metastasis or recurrence38Priestley P. Baber J. Lolkema M.P. Steeghs N. de Bruijn E. Shale C. Duyvesteyn K. Haidari S. van Hoeck A. Onstenk W. Roepman P. Voda M. Bloemendal H.J. Tjan-Heijnen V.C.G. van Herpen C.M.L. Labots M. Witteveen P.O. Smit E.F. Sleijfer S. Voest E.E. Cuppen E. Pan-cancer whole-genome analyses of metastatic solid tumours., 39Puram S.V. Tirosh I. Parikh A.S. Patel A.P. Yizhak K. Gillespie S. Rodman C. Luo C.L. Mroz E.A. Emerick K.S. Deschler D.G. Varvares M.A. Mylvaganam R. Rozenblatt-Rosen O. Rocco J.W. Faquin W.C. Lin D.T. Regev A. Bernstein B.E. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer., 40Leung M.L. Davis A. Gao R. Casasent A. Wang Y. Sei E. Vilar E. Maru D. Kopetz S. Navin N.E. Single-cell DNA sequencing reveals a late-dissemination model in metastatic colorectal cancer. may become necessary to assist clinicians in fully understanding a patient's cancer behavior. The recent COVID-19 pandemic has also highlighted th