Rapid progress is being made in discovering the genetic basis of disease, but test development is not keeping pace. The CETT Program facilitates the translation of genetic tests from the research setting to Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories through collaborations among clinicians, laboratories, researchers, and disease-specific advocacy groups. The CETT Programs Mission is:

• To promote the development of new genetic tests for rare diseases.
• To facilitate the translation of genetic tests from research laboratories to clinical practices.
• To establish collaborations and provide education about each rare genetic disease, related genetic research, and the clinical impact of testing.
• To support the collection and storage of genetic test result information in publicly accessible databases to leverage the information into new research and new treatment possibilities.

In 2003, the Office of Rare Diseases Research (ORDR) of the National Institutes of Health (NIH) became aware of the limited movement of research tests to clinical laboratories. There also was an issue with research laboratories providing test results to individuals, families, and clinicians who were requesting clinical testing. This was a problem because many research laboratories are not focused toward providing clinical services; are not certified by CLIA, which regulate all laboratory testing on humans; do not have clinically trained staff to give test results; and do not have the resources within their research grants to absorb the costs of providing clinical testing.

Increasingly, Institutional Review Boards (IRBs), which protect human subjects in research projects, were appropriately restricting the ability of research laboratories to provide results of genetic testing within their clinical research protocols. Between late 2003 and 2005, ORD, along with Centers for Disease Control and Prevention (CDC), Emory University, American Society of Human Genetics (ASHG), American College of Medical Genetics (ACMG), Society for Inherited Metabolic Disorders (SIMD), Genetic Alliance (GA), and others, commenced a series of activities to address the issue of moving rare disease genetic test translation from the research setting into clinical laboratories and services. This work culminated in the development of the CETT Program.

Meanwhile, in 2005 the U.S. House Appropriations Committee asked ORD to address its concern on the lack of development of diagnostic tests for rare diseases.

ORD held discussions with the Trans-NIH Rare Diseases Research Working Groupa group of representatives from the NIH institutes and centersregarding the problem of genetic test translation and possible solutions. A collaboration with Federal agencies, professional associations, patient advocacy groups, and interested clinicians and scientists was established to explore issues around the access to quality genetic testing for rare disorders. A pilot program was developed within the NIH intramural program to translate rare disease genetic tests at the request of NIH researchers.

From the above noted activities, a number of key issues became apparent with regard to access to quality genetic test translation, some of which go beyond the actual test translation. These include:

• Lack of understanding and appropriate interpretation of CLIA and the Health Insurance Portability and Accountability Act (HIPAA) privacy act among research laboratories, patient groups, clinicians, IRBs, and others that a genetic test result is clinical information that can only be given to an individual through a CLIA-certified laboratory.
• Significant concern for the loss of important clinical and detailed genetic information in the rare disease populations when testing is done within a clinical service setting, as opposed to a research laboratory.
• The need for expert support in test result interpretation and referral, coordinating referrals of individuals with atypical results back to research laboratories for further research studies, and providing educational materials for clinicians and individuals and families with a rare disease to understand genetic tests and what expertise and resources are available.
• Perceived difficulties with obtaining third-party reimbursement for genetic testing, even when obtained in a CLIA laboratory.
• Providing the same level of quality assurance and quality control for low-volume rare disease testing where standard quality assurance and quality control procedures may not be possible.

From these considerations, the CETT Program was developed as a 2-to-3-year pilot program for genetic test translation that would encompass a social context for genetic testing, would be integrated across the NIH, and could become a model process for rare disease test translation that would be useful to the community in general, regardless of whether ORD funds the actual test translation.

Rationale for Developing the CETT Program:

• Most clinical laboratories performing rare genetic disease testing have limited development funds for new tests and limited personnel dedicated to new test development.
• Most clinical laboratories do not have the resources needed for data collection and educational material development.
• Many researchers are not aware of clinical laboratories that can transition the testing developed in their research laboratory.

The CETT Program Will:

• Develop some measure of when a test is "ready for prime time" based on the mutation detection rate and the relationship of proposed new tests to existing tests; currently this is strictly the decision of a laboratory director.
• Support the notion of "truth in advertising" by requiring quality test result reporting that clearly explains the detection rate and other limitations of the test and helps the affected individual and clinician understand the meaning of both "negative" and "positive" test results.

The CETT Program model is to require applicants requesting funds for test translation to form a CETT Collaborative Group comprised of a clinical laboratory, a researcher, an expert clinician, and advocacy representation for the rare condition.

The CETT Program requirements that the test be translated using a CETT Collaborative Group, that information be provided on the possible health care impact or changes in the diagnostic pathway with testing, that the researcher and clinical laboratory coordinate activities, and that data on clinical symptoms be collected with each sample make the CETT Program a new paradigm of test translation. The application can be spearheaded by any member of the CETT Collaborative Group: clinical and/or research laboratories, clinicians studying the rare diseases, or disease-specific advocacy groups. Once the collaborative group has agreed to work together they can register in CETTrack and apply to the CETT Program for funds to develop new clinical tests for rare genetic diseases.

The CETT Program evolved out of a series of Rare Disease meetings (see Background). In the development process the CETT Program received the support of the following groups:

• American Society of Human Genetics (ASHG)
• American College of Medical Genetics (ACMG)
• Association for Molecular Pathology (AMP)
• Genetic Alliance (GA)
• National Organization of Rare Disorders (NORD)
• National Institutes of Health (NIH)
• Centers for Disease Control and Prevention (CDC)
• Health Resources and Services Administration (HRSA)
• Centers for Medicare/Medicaid Services (CMS)
• Human Genome Variation Society (HGVS)
• Food and Drug Administration (FDA)
• Society for Inherited Metabolic Diseases (SIMD)

Just as the CETT Program develops collaborations, the CETT Program Staff itself is a collaboration of people from diverse backgrounds. The CETT Program Staff includes a pediatric neurologist, a genetic counselor, two molecular geneticists, and a medical geneticist. The CETT Program Review Board includes genetic professionals who are clinicians and laboratory professionals, researchers, patient advocates, and primary health care providers.

The CETT Program Staff Includes:

Andy Faucett, M.S., C.G.C.
CETT Program Coordinator

William A. Gahl, M.D., Ph.D.
CETT Program Scientific Advisor

Suzanne Hart, Ph.D.
CETT Program Scientific Advisor

Roberta Pagon, M.D.
CETT Program Review Board Coordinator

Lisa Forman, Ph.D.
National Library of Medicine’s National Center for Biotechnology Information (NCBI)

Kate Reed, M.P.H., Sc.M.
CETT Program Education Coordinator

The CETT Program Review Board Includes:

Leslie Biesecker, M.D.
National Human Genome Research Institute, NIH

Peter Byers, M.D.
University of Washington; American Society of Human Genetics

Tina M. Cowan, Ph.D.
Stanford Biochemical Genetics Laboratory

John Hardy, Ph.D.
National Institute on Aging, NIH

Howard Levy, M.D.
Johns Hopkins University

Rosalie Lewis
Dystonia Medical Research Foundation

Leigh LoPresti, M.D
Medical College of Wisconsin

Elaine Lyon, Ph.D.
Medical Director: ARUP Molecular Pathology Laboratories

Katherine McCurdy
Barth Syndrome Foundation, Inc.

Marshall Summar, M.D.
Medical Genetics, Vanderbilt

V. Reid Sutton, M.D.
Baylor College of Medicine in Houston

Dan Tagle, Ph.D.
National Institute of Neurological Disorders and Stroke, NIH

Tracy Trotter, M.D.
San Ramon Valley Primary Care

Vivianna Van Deerlin, M.D., Ph.D.
University of Pennsylvania Health System

Patricia Ward, M.S.
Baylor College of Medicine

Vicky Holets Whittemore, Ph.D.
Tuberous Sclerosis Alliance

Marc Williams, M.D.
Intermountain Health Care