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Special Reports |
Abstract
Increasing knowledge of the molecular basis of disease and advances in technology for analyzing nucleic acids and gene products are changing pathology practice. The explosion of information regarding inherited susceptibility to disease is an important aspect of this transformation. Pathology residency programs are incorporating molecular pathology education into their curricula to prepare newly trained pathologists for the future, yet little guidance has been available regarding the important components of molecular pathology training. We present general goals for pathology training programs for molecular pathology education. These include recommendations to pathology residents for the acquisition of both basic knowledge in human genetics and molecular biology and specific skills relevant to microbiology, molecular oncology, genetics, histocompatibility, and identity determination. The importance of residents gaining facility in integrating data gained via nucleic acid based-technology with other laboratory and clinical information available in the care of patients is emphasized.
The practice of anatomic and clinical pathology is being transformed by new knowledge in molecular pathology and human genetics and by advances in the application of molecular biology technology. As this trend accelerates, pathology residency programs must address the need to incorporate molecular pathology training and education within their curricula. This is true not only of traditional resident rotations within the anatomic and clinical laboratories such as hematopathology, microbiology, and histocompatibility, but also in new areas of human genetics.1, 2, 3 On one hand, the ability to replace traditional methodologies with more sensitive nucleic acid-based assays is changing clinical laboratories from within. On the other hand, new knowledge of the mutations responsible for classical inherited disorders and mutations defining inherited susceptibility and resistance to common multifactorial disorders is providing novel roles for the clinical laboratory in disease diagnosis and patient management. This new understanding of the genetics of complex diseases such as neurodegenerative and thromboembolic disorders will find use in diagnosis, prognosis, and therapy.4, 5 Similar information about inherited and acquired genetic alterations in neoplasia will alter pathology practice and clinical management of these disorders.6, 7
The importance of pathologists gaining facility with advances in molecular pathology and human genetics and incorporating this information within the routine practice of pathology is difficult to overstate. Pathologists must be adequately prepared to offer these clinical services and assume leadership roles in molecular pathology research and education. Pathology residency programs have responded to this challenge by devising a number of strategies for preparing residents for practice in this new era. A survey conducted by the Association for Molecular Pathology (AMP) polled United States pathology training programs regarding their efforts at molecular pathology education.8 More than 80% of programs indicated that they have already instituted educational programs for molecular pathology. These programs are quite variable in form, ranging from formal 2- to 3-month clinical rotations in a general molecular pathology laboratory to short didactic sessions organized cooperatively with other departments. This variability is likely due in part to the heterogeneous nature of training programs and the residents they serve. However, program directors completing the survey frequently pointed out the need for more information concerning what constitutes appropriate molecular pathology education and the infrequent discussion of this topic in the literature.2, 3
In this report, the Training and Education Committee of AMP provides an outline of important elements of resident molecular pathology education. Training requirements for fellowships in molecular pathology are not delineated in this paper. Residency directors may wish to consider this outline as they implement and refine the molecular pathology components of their programs. We have focused on broad concepts important to education in this field rather than compiling extensive lists of the numerous diagnostic assays now available. Literature references given in the text and reading suggestions for residents linked to specific areas within molecular pathology are intended as representative examples and entry points to the relevant literature for molecular pathology education, rather than as a comprehensive listing of available teaching materials or citation of the primary literature.
Concepts, Technologies, and Instrumentation for Molecular Pathology
The practice of molecular pathology requires understanding of general concepts and technologies that are common to specific applications in each area of the clinical laboratory. Access to this basic information will serve residents well not only during their training but also as practicing pathologists as new areas of molecular pathology are developed.
Basic Molecular Biology and Human Genetics Concepts
Many residents enter pathology training with sophisticated
backgrounds in molecular biology and human genetics obtained from
research experiences, graduate programs, and medical school
courses.9
However, a significant fraction of pathology
residents do not share this background. In the absence of such
experiences, and in light of the fact that human genetics and molecular
biology education in United States medical schools remains uneven, an
emphasis on concepts underlying molecular pathology is helpful to many
pathology residents. Knowledge of the basic molecular biology
information listed in Table 1
will aid residents in understanding the technology employed for
molecular pathology practice in general and for specific applications
in areas such as infectious disease diagnosis and
hematopathology.10
Knowledge of the concepts in human
genetics given in Table 2
will be useful to residents as they encounter molecular pathology
applications in histocompatibility and human identification and is
essential for clinical applications in inherited disease diagnosis and
cancer genetics.11, 12
As noted above, the increasing role
of the clinical laboratory in the detection of alleles associated
with multifactorial disease resistance and susceptibility requires that
pathology residents have a relatively sophisticated understanding of
human genetics.
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.13, 14, 15, 16, 17
In order to understand problems associated with
specific assays and issues of test sensitivity, specificity, and cost
in a molecular pathology laboratory, residents should understand the
major instrumentation commonly employed. These include
spectrophotometers, gel electrophoresis equipment, thermal cyclers,
automated DNA sequencers, oligonucleotide synthesizers, and
hybridization apparatus.18
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molecular biology techniques such as
library screening by hybridization, subcloning, the transformation of
Escherichia coli with plasmids, and the isolation of cloned
DNA fragments from hosts, since these are generally labor intensive
methods which are not commonly used in contemporary clinical molecular
pathology laboratories. However, residents will wish to familiarize
themselves with these methods, at least through their
readings.10
These methods provide a conceptual and
historical basis for the techniques in Table 3
and are useful today for
research purposes and for occasional diagnostic problems. Education within Specific Areas of Molecular Pathology
Opportunities to provide educational experiences in molecular pathology for residents most often occur in areas of the clinical laboratory in which molecular technology and concepts are having a major impact. Examples include, but are not limited to, the diagnosis of inherited disease, leukemia and lymphoma diagnosis and monitoring, solid tumor analysis, infectious disease testing, HLA allele identification for transplantation, and identity and paternity determination. Some programs will not be able to provide a complete array of diagnostic experiences for residents. If clinical services in a particular training program are limited to a single area or application within molecular pathology, it may be difficult to construct an educational program of adequate breadth. Programs in which at least three molecular pathology areas or applications are represented in the clinical laboratory, especially when one involves inherited disease diagnosis, are likely to provide adequate case material for resident education. For each major area of molecular pathology, it is possible to define important elements of resident education.
Infectious Disease Testing
The molecular pathology tests performed most frequently in clinical laboratories today are in the field of infectious diseases. The marked improvement in sensitivity of nucleic acid-based detection of infectious agents and the rapid turnaround time as compared with some culture or antigen detection methods has argued for a stronger representation of molecular techniques in many laboratories. Molecular methods for quantitation of infectious agents, identification of difficult or impossible to cultivate agents, identification of antibiotic or antiviral resistance genes, and identification of toxin genes are becoming commonplace in laboratories. On the other hand, traditional microbiologic methods continue to be the appropriate approach for identifying most infectious agents, particularly from a cost-effectiveness perspective. The management of microbiology and virology laboratories now requires that laboratory directors have appropriate training in molecular biology so that they effectively make choices among the variety of technologies, including nucleic acid-based tests, available to them. Clinical rotations in these disciplines in residency training programs should be designed to accommodate this reality. Residents need to have basic understanding of the following:
• Organization of the DNA/RNA genomes of infectious agents
• Evolutionary relationships among microorganisms
• Species and genus specific sequences
• Genetic basis of pathogenesis and drug resistance
Examples of commonly employed DNA/RNA-based infectious disease tests include those designed to detect and quantitate human immunodeficiency virus-1, hepatitis C virus, cytomegalovirus, herpes simplex virus types I and II, Epstein-Barr virus, Chlamydia trachomatis, Neisseria gonorrhea, and Mycobacterium species.
Many training programs function in clinical settings where a subset or only a few of these assays are offered as diagnostic tests; however, a limited array of molecular microbiology assays can still serve as a reasonable basis for teaching residents important general concepts relevant to the use of nucleic acid-based tests. The concepts taught should be beyond the issues of organism detection and quantitation, since molecular techniques are also useful for other purposes in the microbiology laboratory. For example, residents should gain an appreciation of the clinical utility of differentiating among strains of fungi and bacteria with technology such as pulsed-field gel electrophoresis, ribotyping, and restriction fragment length polymorphism analysis in epidemiological studies. Similarly, direct and indirect DNA sequence analysis for purposes of genotyping and assessing drug resistance is clinically relevant.
Correlation of diagnostic and quantitative molecular test results with standard microbiological methods and clinical findings should be emphasized for best appreciation of the important applications of each. Training should include opportunities to discuss a variety of examples of the use of molecular methods to identify and characterize infectious agents. Residents should have experiences which allow them to do the following:
• Interpret the detection of the nucleic acids of an infectious agent that should not be present in a clinical sample
• Interpret the meaning of an infectious agent detected in a clinical sample for which it may or may not be a pathogen (pathogen versus colonization or carrier)
• Interpret the results of a method designed to quantitate infectious burden in clinical samples
• Interpret the results of a method designed to identify sequence variation associated with antimicrobial or antiviral resistance
• Interpret the results of a method designed to classify a microbe based upon phylogenetic data
• Interpret the results of a molecular epidemiological investigation as to the likelihood of a common point exposure
• Interpret the results of in situ hybridization in the context of morphologic features and clinical data
The trainee should become familiar with the importance and unique
aspects of quality control and proficiency testing required for
molecular tests for infectious agents that are also potential
environmental contaminants. Emphasis should be placed on aspects of
appropriate specimen selection, integrity of samples, specimen
preparation, contamination prevention, and monitoring the sensitivity
and specificity of assays. Table 4
provides selected readings in molecular microbiology which residents
may find useful.
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Substantial advances in knowledge of the biology of leukemias and lymphomas, embodied in part in the increasingly detailed information regarding the genetic alterations contributing to the development of these neoplasms, have been particularly important in the field of hematopathology. Similar advances in our understanding of the molecular genetics of solid tumors are having a significant impact on the pathologist’s approach to these neoplasms. Finally, recent discoveries of inherited alterations in tumor suppressor genes and genes encoding proteins responsible for DNA repair and their association with neoplasms such as breast and colon adenocarcinomas have opened a new and controversial arena of clinical assays for cancer predisposition assessment. It is essential that pathologists understand the molecular basis of neoplasia including the contribution of both inherited and acquired genetic alterations to tumor development. Important concepts relevant to molecular oncology include the following:
• The clonal origin of neoplasms and the phenomenon of clonal evolution
• The multistep pathogenesis of neoplasia involving:
• inherited predisposition
• activation of oncogenes
• inactivation of tumor suppressor genes
• alterations of genes regulating apoptosis
• mutations of DNA repair genes
Residents should understand the spectrum of genetic alterations
associated with neoplasia and be conversant with techniques for
detecting different classes of mutations. They should be aware of the
variety of means by which oncogene activation and tumor suppressor gene
inactivation contribute to malignant cell growth. They should have some
familiarity with specific examples of gene alterations found in common
neoplasms. Residents should discuss the phenomenon of loss of
heterozygosity including its detection and consequences. Residents
should be familiar with chromosome translocations associated with
specific neoplasms. This is particularly true for translocations
involving genes such as PML/RAR-
, EWS/Fli1, bcr/abl, bcl-2, and the
T cell antigen receptor and immunoglobulin loci which have played
important roles in the development of improved understanding of the
pathogenesis of neoplasia and which are useful in making diagnostic,
prognostic, and therapeutic decisions. The advantages and disadvantages
of detecting chromosome translocations and their chimeric products via
traditional cytogenetics, molecular cytogenetics, and amplification
techniques such as reverse transcriptase-PCR should be discussed.
Residents will wish to gain experience in the detection of clonality in lymphoproliferative lesions via immunoglobulin and T-cell receptor gene rearrangement analysis and the integration of these results with morphologic and other clinicopathologic data to produce a cohesive diagnostic report. Residents should review the process of normal rearrangement of the immunoglobulin and T-cell antigen receptor genes during B- and T-cell development. The advantages and disadvantages of detection of clonal rearrangements via Southern hybridization versus PCR approaches should be discussed. The value of gene rearrangement analysis in the context of morphologic, immunohistochemical, and flow cytometric study of lymphoproliferative lesions should be considered.
Diagnostic molecular oncology goes beyond the detection of
translocations, identification of mutations in oncogenes and tumor
suppressor genes, and clonality studies. Residents should gain
familiarity with the use of amplification-based tests to detect minimum
residual disease and should consider how one judges the clinical
relevance of these data. They may gain exposure to microsatellite
allele assessment for purposes of assessing genomic instability
associated with DNA repair enzyme mutations or to determine the success
of engraftment following allogeneic bone marrow transplantation.
Finally, the promises and pitfalls of the ability to make predictions
of the future risk of cancer by detecting inherited mutations in genes
such as BRCA-1 will be of interest. Predisposition
testing for the inherited cancer syndromes raises many of the issues
discussed in the subsequent inherited disease section. Table 5
and 6
give selected examples of readings in solid tumor and hematopathology
molecular oncology which residents may find useful.
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Diagnostic assays are now available to detect mutations responsible for many classic inherited syndromes. Mutations which contribute to several common multifactorial disorders are also known. Like other sections within the clinical laboratory, molecular pathology laboratories performing tests to detect mutations associated with inherited disease have responsibilities beyond the production of a test result. Laboratory programs offering human genetic analysis must be designed and managed with great care, since these services very often involve prenatal diagnosis, presymptomatic diagnosis, implications for families as well as individuals, frequent consultation with referring non-specialist providers, and unique ethical issues. Resident education in inherited disease diagnosis should emphasize these issues in addition to teaching useful technologies.
In this regard, training programs should offer residents opportunities for significant interaction with human geneticists, genetic counselors, and other clinicians providing genetic services. These interactions should be designed to offer exposure to issues relevant to genetic diagnosis and counseling, risk assessment, explanation of testing and results to patients, psychosocial assessment, and support services. The resident should be exposed to clinical experiences which illustrate the problem of obtaining meaningful informed consent, the potential for genetic discrimination, issues concerning predictive testing in presymptomatic individuals, and the implications of genetic testing in minors. In some cases experiences on clinical genetics services may provide this exposure. In other settings, interdisciplinary conferences may be more suited to this purpose. These experiences should be designed to prompt the resident to consider the inherent complexities in the use of genetic information in the care of patients and families.
An introduction to inherited disease diagnosis should include a number
of concepts and practical issues which build upon residents’ knowledge
of the basic information in Table 2
:
• The use of standard molecular laboratory methods to detect point mutations, deletions, and other mutations responsible for disorders such as cystic fibrosis, Factor V Leiden associated hypercoagulability, hemochromatosis, and the muscular dystrophies should be studied.
• The transmission of genotypes and phenotypes in families with classic Mendelian disorders as well as non-classical disorders which display genetic imprinting or anticipation should be studied.
• The benefits and drawbacks of the use of samples other than peripheral blood such as buccal smears for inherited disease diagnosis should be considered.
• Potential problems such as maternal contamination associated with diagnostic tests performed with samples such as amniocytes obtained for prenatal diagnosis should be emphasized.
• Risk assessment in families via linkage analysis when direct mutation detection is not possible or feasible should be discussed.
• Concepts of risk analysis should be reviewed for selected disorders with an emphasis on the general characteristics of Bayesian analysis and computer-based risk assessment.
• Problems posed for interpretation of the consequence of mutations detected in single gene and multifactorial disorders displaying incomplete penetrance or variable expressivity should be considered.
Cloned disease genes and specific mutations are now known for a
large number of inherited disorders, making molecular diagnosis
feasible in many cases. Table 7
includes a highly selected set of readings which residents may
initially employ as they introduce themselves to this field.
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Laboratories providing support for transplantation programs have
undergone a major transformation during the past decade as DNA-based
forms of HLA Class II allele identification have replaced serologic
detection of Class II antigens for routine characterization of organ
and hematopoietic stem cell recipients and donors. Allele
identification, rather than antigen detection, will become routine for
the Class I loci as well during the next few years. These changes are
driven by nucleic acid-based typing’s heightened accuracy and
precision in comparison to serology. A diverse array of methods has
been applied to clinical HLA allele identification, including sequence
specific PCR, sequence specific oligonucleotide hybridization, and DNA
sequencing of PCR products. The adoption of these methods in the HLA
laboratory has implications for resident education. Residents need to
understand and work with a variety of concepts and issues relating to
molecular histocompatibility (see Table 8
for selected readings). These include:
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• The nature and consequences of the extensive polymorphism of the Class I and Class II genes
• Nucleic acid-based methods for identifying HLA alleles and appropriate choices of methods tailored for specific clinical applications
• The relationship of alleles to antigens expressed on cell surfaces as detected by serologic methods and problems posed by alleles which are not expressed (null alleles)
• The utility of Class I and Class II allelic information gathered at various levels of resolution and its clinical value in hematopoietic stem cell, renal, and the other forms of solid organ transplantation
• The consequences of allelic mismatches in terms of failure to engraft, graft rejection, and graft versus host disease
Identity Determination
The recent characterization of an extensive array of
microsatellite, minisatellite, and single nucleotide polymorphisms
distributed throughout the human genome has yielded many loci useful
for distinguishing among individuals. Serologic-based red blood cell
and HLA antigen detection for purposes of paternity and forensic
identification has been supplanted by Southern hybridization and
amplification mediated analysis of polymorphisms. Identifying alleles
at polymorphic loci is also useful for assessing engraftment in
allogeneic transplantation, performing linkage analysis in families,
detecting loss of heterozygosity in tumors, and for resolving
diagnostic specimen mixups. A variety of nucleic acid-based methods
have been developed for these purposes (Table 9
,selected readings).
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• Residents should be familiar with the uses of polymorphism assessment to conduct genetic linkage analysis and paternity and forensic analyses.
• Residents should understand the statistical concepts useful for calculating the probabilities of relatedness and identity.
Clinical Correlation
The importance of training residents in the appropriate interpretation of molecular pathology test results and their integration with other laboratory data in the clinical context has been illustrated in the discussions of individual applications above. The need for close attention to clinical correlation of molecular pathology data is highlighted by the relative novelty of many molecular technologies and the recent introduction of many molecular pathology tests. Education in molecular pathology should offer opportunities for residents to critically examine what, if any, additional valuable information a nucleic acid-based test will provide in a particular clinical situation over traditional methodologies:
• How is the proposed molecular test more sensitive or more rapid than an established test?
• When is the contemplated nucleic acid-based test the only practical way to obtain the needed information?
• If not appropriate as a general approach to a clinical problem, when is the DNA-based assay most suited to a particular diagnostic niche? For example, detection of HIV-1 RNA via amplification strategies may be ideal in neonates because of the presence of maternal antibodies, but not appropriate as an initial approach in the general population.
• When do the very specific questions answered by nucleic acid-based methodologies merit their substitution for broader traditional screening methods?
• How well do assays for known mutations associated with inherited disorders adequately address the possibility of unexpected genetic heterogeneity?
• Does the detection of the genome of a microorganism via a DNA amplification technique precisely correlate with the presence of a clinical significant infection?
• What are the implications for family members of a patient with a positive result for a specific genetic disease?
• How does a DNA-based test result correlate with other available laboratory and clinical data?
Well designed molecular pathology education programs should allow ample opportunity for discussion of and practical experiences relevant to these and related questions.
Laboratory Management
Like other laboratory rotations, molecular pathology residency training should include opportunities to learn about quality management, test reimbursement, and the efficient organization of the laboratory.19, 20 However, molecular pathology laboratories also offer several distinctive laboratory management teaching opportunities. Residents can learn how priorities are set for the local development and validation of new genetic tests based on information only recently available in the literature. They can develop some facility in using computer technology and internet-based databases which provide gateways to exponentially accumulating information regarding the sequence of the human genome, mRNAs present in various cell types, DNA polymorphisms, and correlations between specific genetic variations and disease states.21 Residents can consider strategies for recruiting and training molecular pathology technologists given the reality that few medical technology programs include molecular pathology training. Finally, the fact that blood, cell, and tissue specimens constitute banked DNA samples22, 23 linked to individual patients raises important management issues which should be addressed. These include discussion of means for preserving patient privacy, maintaining confidentiality, and appropriately protecting and compartmentalizing access to clinical genetic results stored and communicated in paper and electronic forms.24
Curricular Choices for Resident Molecular Pathology Education
Molecular pathology education experiences for residents will necessarily vary among programs. These differences are driven by variation in faculty expertise, the mix of specific molecular diagnostics services offered, residents’ prior experiences and interests, and opportunities for coordinated programs with other departments within the institution. While substantially different approaches are taken, it is apparent from the survey of residency directors referred to above that a substantial majority of training programs across the United States consider it necessary to offer residents formal education in molecular pathology. Appropriate programs would reasonably include various combinations of didactic sessions, rotations within molecular pathology laboratories, participation in conferences, and experiences on relevant clinical services. While didactic sessions may substitute for practical experience in the laboratory because of the lack of a particular molecular pathology service at a training institution, the wholesale teaching of molecular pathology through written materials and lectures seems as inappropriate in this field as for any of the traditional anatomic and clinical pathology rotations. The physical location of molecular pathology education will also reasonably vary among programs secondary to differences in the organization of molecular pathology services. Some institutions have developed centralized molecular pathology facilities while others provide these services in preexisting sections of the clinical laboratory. For example, topics in molecular virology might be addressed either in the microbiology laboratory rotation or in the molecular pathology laboratory rotation or both depending on where the relevant tests are offered. In institutions in which molecular tests are performed in a molecular pathology laboratory, many of the educational goals discussed in this report can be achieved in rotations through that laboratory. However, an added emphasis on appropriate integration of data from other sections of the laboratory and clinical correlation will be necessary. Conversely, in institutions in which molecular pathology practical experience is gained in dispersed laboratories, a coordinated strategy for providing the general training in basic technologies and concepts in molecular and human genetics described above must be devised.
Pathology residency programs may wish to develop educational experiences which allow residents to meet several goals:
• Understand the basic concepts of human genetics, molecular biology and cell biology
• Develop a familiarity with the principles and techniques used in the design and validation of molecular patient tests25
• Understand the specimen requirements for molecular tests26, 27
• Develop competency in test interpretation
• Understand the clinical applications of molecular testing and the appropriate role of nucleic acid-based testing relative to other methodologies
• Develop familiarity with personnel requirements and management strategies necessary for efficient operation of a molecular pathology laboratory
• Be aware of important legal, ethical, and social implications of the availability of tests which assess human genetic variability
Resources for Molecular Pathology Education
Many residency programs will not be in a position to directly expose residents to all major areas of molecular pathology. This fact suggests that external resources for molecular pathology education will be important supplements to case material available within each program. Several textbooks dealing with molecular pathology are currently available.18, 28, 29, 30 These subjects are also addressed in texts specific to disciplines such as hematopathology. However, texts dealing with topics in molecular pathology become rapidly outdated given the rate of change in the field. Professional organizations within pathology such as the American Society of Clinical Pathology (ASCP), the College of American Pathologists, the American Association of Clinical Chemistry, the International Academy of Pathology, and the Association for Molecular Pathology (AMP) provide a number of excellent molecular pathology courses at annual meetings. An intensive, practical course in molecular pathology has been offered for several years by the American Society for Investigative Pathology. The ASCP’s Check Sample series on Molecular Pathology and Applied Technologies provides instructive relevant case material. Each of these resources is valuable; however, educational materials for molecular pathology are somewhat limited in number and scope. The development by interested organizations and institutions of additional patient case-based resources useful to training programs and residents, especially materials that could be made available in electronic format, would be of substantial benefit.
Summary
Education in molecular pathology is an important component of modern pathology training programs. We have presented a view of general topics and issues specific to fields within molecular pathology which should be addressed in residency rotations. Few, if any, programs will be able to offer residents all of the experiences which we have outlined above. Programs should not interpret the goals and objectives outlined in this paper as ones which must be comprehensively satisfied in order to offer successful education in molecular pathology to residents. However, creative and selective coverage of this material in designated molecular pathology rotations in conjunction with traditional anatomic and clinical laboratory rotations and appropriate clinical experiences outside the pathology laboratory should enable many programs to devise adequate programs. We expect that training programs will draw upon the diverse nature of their clinical services and faculties to create a rich variety of approaches to resident molecular pathology education, linked by a goal of preparing new pathologists to succeed in the era of molecular medicine.
Footnotes
Address reprint requests to Thomas M. Williams, M.D., Department of Pathology, Basic Medical Sciences Building, Room 327, University of New Mexico Health Sciences Center, 915 Camino de Salud, Albuquerque, NM 87131-5051. E-mail: twilliams{at}salud.unm.edu
Contributors: Thomas M. Williams (Chair), Frank Burns, Domnita Crisan, J. Steven Dumler, Louis M. Fink, Thomas S. Frank, Timothy Greiner, Jeffrey A. Kant, Vickie Matthias-Hagen, and Linda Sabatini.
Accepted for publication July 15, 1999.
References
This article has been cited by other articles:
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  B. R. Smith, A. Wells, C. B. Alexander, E. Bovill, S. Campbell, A. Dasgupta, M. Fung, B. Haller, J. G. Howe, C. Parvin, et al. Curriculum Content and Evaluation of Resident Competency in Clinical Pathology (Laboratory Medicine): A Proposal Clin. Chem., June 1, 2006; 52(6): 917 - 949. [Abstract] [Full Text] [PDF]
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