U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

Reporting DNA-Based Genetic Test Results Applicable to Heritable Conditions

and/or Markers of Drug Metabolism:  The Clinical Laboratory Report as a

Decision-Support Tool

Announcement Type:  New

Funding Opportunity Number: CDC-RFA-CI07-709

Catalog of Federal Domestic Assistance Number:   93.064

Application Deadline: August 31, 2007

Executive Summary: Advances in the field of human genomics has fostered the development of an increasing number of clinically offered DNA-based tests applicable to heritable conditions and markers for drug metabolism.  From a public health perspective, it is hoped that these tests improve the capacity to identify persons who have or are at higher risk for disease or exhibit differences in drug responses so interventions can be applied to reduce morbidity and mortality in relevant populations.  An evolving facet of practice is the use of genetic tests in clinical settings that lack ready access to genetic expertise.  For instance, carrier testing for cystic fibrosis, fV Leiden, hemochromatosis, and fragile X are a few of the tests ordered in primary care settings.  This has raised concerns that clinicians in such settings are using these tests without the knowledge or tools to best serve their patients which ultimately may compromise the public health benefits sought.  The focus of this announcement is to develop and evaluate a framework for reporting genetic test results that provides a basis for clinical decision support most applicable to laboratories preparing such reports, those developing and supporting educational and informational resources, and clinicians ordering such tests who may be less informed about the nuances of genetic testing.  The significance of this can be recognized in considering that DNA-based tests for heritable conditions fall into that category of testing in which the meaning of the result, in this case, a genotype, is not self evident without an interpretive component.   For genetic tests, the interpretation can clarify such issues as residual risk, detection rate, genotype/phenotype correlations, metabolizer status, implications for other family members, consistency with a suspected diagnosis, etc.  Professional guidance does exist that specifies what information elements should be included in a test report (i.e., the reason for testing, information about the patient, family, genotypic association with disease, the characteristics of the test used, test result, etc.) but provides minimal advice as to how these should be integrated to effectively communicate the clinically relevant concepts.  Therefore, this FOA solicits applications that will serve to 1) identify a set of clinical principles that are critical to effectively communicate between laboratory and clinical settings important for achieving desired patient outcomes, 2) select DNA-based tests currently offered in a clinical setting useful as models in defining how clinically relevant information can be effectively communicated, 3) develop test reports designed to integrate information elements (as recommended by professional guidelines (i.e., American College of Medical Genetics (http://www.acmg.net/resources/policy-list.asp), Clinical Laboratory Standards Institute (MM-01A2 Molecular Diagnostic Methods for Genetic Diseases; Approved Guideline & MM-09A Nucleic Acid Sequencing Methods in Diagnostic Laboratory Medicine, College of American Pathology Checklist (www.cap.org)), and other sources, as appropriate) into a coherent and uniform interpretation that effectively communicate clinically relevant concepts useful for clinical decision making and/or counseling, 4) identify and/or develop educational and informational resources to support the role of the laboratory in developing laboratory result reports and to clinicians in understanding and applying the test result, and to 5) pilot test and evaluate reports and supportive resources to assess usefulness and satisfaction in laboratory and clinical settings.  It is expected that the successful applicant will build upon the past and current work of professional organizations, investigators, and practice community in addressing the scope of work proposed.    Outcomes from work proposed may be applicable to laboratories, clinical settings, those that develop educational programs and informational resources, those who pay for clinical services, professional organizations developing recommendations, policy makers, and others.  In addition, the scope of work proposed may be applicable to other areas of laboratory medicine where knowledge is rapidly advancing and its integration into practice has been problematic.    

I. Funding Opportunity Description

Authority:   This program is authorized under section 317(k)(2) of the Public Health Service Act [42 USC 247b(k)(2)], as amended.

Background: The Division of Laboratory Systems, NCPDCID, Centers for Disease Control and Prevention, works with the private and public sector to assure the quality of US clinical and public health laboratory practices.  Clinical genetic testing and particularly that pertinent to heritable conditions and markers of drug metabolism is rapidly evolving with an increasing number of tests offered clinically.  As such, there is great interest in identifying where there are unmet needs to assure the quality of such testing and assure desired benefits are achieved and harm is avoided.  The focus of this RFA is to solicit applications that propose approaches to develop and evaluate laboratory reports and where helpful, supportive resources, designed to help laboratories prepare such reports and assist clinicians in understanding the clinically relevant information associated with the test result and its application to clinical decision making and/or counseling.  To achieve this, it is important to recognize that most genotypic (some would say all) test results are in themselves uninformative without integrating other types of information which may include the indication for testing, patient data, family history, genotypic association with disease or metabolic status, and test-specific information.  From this perspective, the test result can be thought of as a component of decision-support for the clinician.  Other factors contributing to decision-support include the clinician's education, knowledge and comfort level in the use of available educational and information resources.  

Professional organizations (i.e., ACMG, CLSI, CAP, etc.) have provided recommendations and guidance for information elements to include in reports that are thought necessary to understand the clinical context of the test result.  These include, among others, indication for testing, mutations tested, detection rate, race/ethnicity, and family history.  On the other hand, professional guidelines provide limited guidance in how such elements should be integrated to effectively communicate the clinically relevant concepts necessary to understand and make clinical management decisions or provide patient counseling.  (It is important to note that in some cases, model reports have been developed and made available for use as is the case for cystic fibrosis.  These can be found as addendums to recommendations pertaining to cystic fibrosis carrier screening developed in a joint effort by the American College of Obstetricians and Gynecologists and the American College of Medical Genetics.  However, the usefulness of these reports has not been evaluated in practice.). 

Although expert consultation exists through geneticists, genetic counselors, and medical specialists, it is anticipated that an increasing number of genetic tests will be or are routinely offered in settings where such expertise is not readily available.  However, such expertise may not always be necessary, particularly for the less complex cases, providing the care provider understands the salient genetic principles.   Such understanding is where the challenge lies.  For instance, DNA-based carrier screening is a commonly ordered test in OB-GYN settings.  Most test results indicate no disease-associated mutations found.  In most cases, this indicates minimal risk for being a carrier.  In some cases, because of family history or the self identified race / ethnicity, the patient's risk may be indeterminate or higher.  Failure to differentiate between these possibilities may provide an inaccurate risk estimate and deny a discussion of other available options to the patient.  In this example, a properly crafted report may be a useful tool in guiding the clinician's understanding of the clinical concepts and their application to patient care.

Several studies have documented potential shortcoming in current reporting practices to implications for patient care and counseling.  For tests relevant to heritable conditions, concerns have been raised in how 1) reports communicate residual risks, and 2) reports communicate the uncertainty associated with diagnostic tests in which the genotypic result is no conclusive (i.e., finding of heterozygosity for an autosomal recessive condition, finding of a sequence variant of unknown significance).  A test report's clarity to its clinical relevance for the patient can depend upon how critical information elements are integrated.  These elements can include family history, race/ethnicity, clinical presentation, and knowledge of the genotype/phenotype correlation; inclusive of penetrance and expressivity.  For tests measuring drug metabolism status, other issues arise such as what is known about the patient's clinical situation, specific knowledge about the drug under question, and drug-drug interactions when multiple modalities are in play.  This lack of understanding has been attributed to the rapidly evolving field of clinical and laboratory genetics and educational shortcomings within the medical community.  

Studies have documented variability in laboratory reports in terms of format, content, and use of terminology and nomenclature.  These findings have raised concerns about the potential risk for misdiagnoses and/or failure to appropriately apply test results to clinical decision-making and counseling.  Another issue raised is whether reports are sufficiently detailed and clear for all persons who may use the report in a way that influence care of the patient.  While the laboratory director and patient's health care provider are the usual responsible parties, other staff is involved in various aspects of preparation and review of the report and communication with the patient.   The report may also move among various medical practices where again it will be important that the indication for testing and interpretation be clearly and uniformly understood.  These observations raise the question of staff competency and the need to have reports constructed to be understood by all who may use them.

These challenges are not unique to the field of genetic testing, and to some extent have been addressed in other areas of laboratory medicine.  For instance, in the field of surgical pathology, coordinated efforts between oncologists and surgical pathologists have resulted in the development of "synoptic" reports.  The characteristic of a synoptic report is uniformity in what information elements are included and how they are integrated to develop a clinically useful interpretation.  Such reports have resulted in improved laboratory and clinician satisfaction and documentation of clinically relevant indicators of process improvement.  (Hammond, EH, Flinner RL (1997) Clinically relevant breast cancer reporting: using process measures to improve anatomic pathology reporting.  Arch Path Lab Med 121:1171-5). 

Purpose:  The purpose of this RFA is to solicit applications proposing to develop and pilot test genetic test reports designed to integrate genotypic results pertinent to heritable conditions and/or markers for drug metabolism into a clear and coherent interpretation that effectively communicates clinically important concepts useful for clinical decision making and/or counseling.  In addition, the successful applicant will identify and explore the usefulness of ancillary support to laboratories and clinicians in the preparation of test reports and understanding of the content.  Ancillary support may include development or leveraging of educational and information resources and/or consultative services.  Support may include identifying, developing, or raising awareness of educational courses, developing and/or providing access to written materials, or information  that can be delivered electronically (web-based resources, distance-learning, etc).  The applicant will devise a process to identify the clinically relevant concepts requiring clear communication and select DNA-based genetic test(s) (choosing among those that are offered clinically) useful as models for the proposed scope of work.  The successful applicant will then facilitate the development of model reports useful as instruments in evaluating the communication of clinically important concepts.  Along with these, the successful applicant will also develop or assemble educational and informational resources useful for laboratory and clinical settings in the evaluation of the model reports (for instance, model guidance to laboratories in how to fill out the report or clinicians in understanding the language contained therein).  The evaluation is expected to focus on the usefulness and satisfaction of model test reports and the utility of supportive educational and informational resources.  As described above, such resources may range from new ones developed under the guidance of the awardee to those already available and accessible.

Tests selected as models for the scope of work proposed should be useful for evaluating the means by which specific clinical concepts are communicated that are important to application of the test result   (i.e., type of inheritance, penetrance, expressivity, classification of rapid versus slow metabolizers, etc).  It may also be useful to consider tests on the basis of their use in various medical settings and disciplines (i.e., rural vs. urban; primary care vs. specialty, populations served, etc.).   Applicants are encouraged to consider those tests that are or beginning to be used in settings that typically lack specialized knowledge of genetics (i.e., primary care). 

The overall scope of work is expected to build upon an active collaboration among clinicians, laboratory professionals and others.   In the performance of the work proposed, applicants may wish to consider active collaboration with professional organizations and other entities that have provided applicable guidance, educational programs, and informational resources to enhance coordination with existing resources.  Although the scope of work is primarily focused on DNA-based testing relevant to heritable conditions and/or markers of drug metabolism, applicants are encouraged to consider the broader implications of their proposed scope of work in light of other areas of laboratory medicine where similar challenges exist.

This program addresses the “Healthy People 2010” focus area(s) of: 1) Educational and Community-Based Programs, 2) Health Communication, and 3) Public Health Infrastructure.

This relates to DHHS GPRA Goal #4: Improve the Quality of Health Care and Human Services and particularly Goal #4.1:  Promote the Appropriate Use of Effective Health Services.

2.      Facilitate partnerships with laboratory professionals, clinicians, educators, health information specialists, health communication specialists, organizational entities, and others, as appropriate, to advise and be part of the proposed scope of work.