Develop guidelines for report distribution.

sensitivity of 0.5%. Another method that can be used for the detection of t(9;22) is Southern hybridization analysis, which reliably identifies the BCR gene rearrangement using probes to the major or minor breakpoint with a sensitivity of about 5%. The reverse transcriptase-polymerase chain reaction (RT-PCR) is the most sensitive method for the detection of t(9;22). Amplification methods are capable of detecting 1 tumor cell among 100,000 normal cells, which makes this test suitable for detection of minimal residual disease. Real-time RT-PCR techniques are now available for a precise quantification of the chimeric transcripts, which has some prognostic value. Before embarking in the development of a particular methodology, it is important to keep in mind the specific disease and the advantages and disadvantages of each procedure for diagnosing that particular clinical condition.

3.2. PATENT ISSUES A large number of in vitro amplification procedures are patented and a license agreement for their use must be obtained; if not, the laboratory using the procedure is liable to prosecution for patent infringement. Traditionally, licensure is obtained for a particular procedure by purchasing an FDA-approved set of reagents sold by a manufacturer that holds the patent or an exclusive license to the amplification process. This approach is very limited for molecular diagnostic tests because there are few tests approved by the FDA. Thus, a laboratory using a particular patented process for clinical use must first negotiate a license agreement with the patent holder.

Almost identical considerations must be given to the use of sequence information required to design an assay. Sequences of newly discovered genes (e.g., human genes and virus genomes) are frequently patented by their discoverers, and the user of the sequence information without a license agreement runs the same risk of liability for patent infringement. Unfortunately, with the current environment and diversity of sources for sequence information, it is not always clear whether the sequence has been patented or who owns the patent. For this reason, before undertaking the development of any test on published sequences where a major commitment of resources is planned, it is advisable to check with the investigators that first described the sequence to determine patent issues. Also, careful review of the patent database and pending patent databases could be very useful (United States Patent and Trademark Office home page:

3.3. ASSAY DESIGN AND DEVELOPMENT Once specific analytes, assay techniques, and specimen types have been identified, the assay design and development can begin. Table 1 describes the different steps of the testing process that need to be taken into consideration when designing an LDT. The first step in introducing an LDT is to optimize each step of the analytical process, which includes nucleic acid extraction, amplification, detection, quantification, and result interpretation. Several review and research articles have provided detailed descriptions of the key parameters that might influence the

Table 2

Guidelines and Standards for Molecular Diagnostics Testing


Guideline or standard


NCCLS MM1-A Molecular Diagnostic Methods for Genetic Diseases

MM2-A Immunoglobulin and T-Cell Receptor Gene Rearrangement Assays MM3-A Molecular Diagnostic Methods for Infectious Diseases MM-5-A Nucleic Acid Amplification Assays for Molecular Hematology MM-6-A Quantitative Molecular Diagnostics for Infectious Diseases MM-7-P Fluorescence in Situ Hybridization Methods for Medical Genetics MM-8-P Measurement and Interpretation of Trinucleotide Repeats

ACMG Standards and guidelines for clinical genetic laboratories: Policy Statements Prenatal Interphase Fluorescence In Situ Hybridization

ACMG Position Statement on Multiple Marker Screening in Women 35 and Older Fragile X Syndrome: Diagnostic and Carrier Testing

Technical standard and guidelines for Fragile X: the first of a series of disease Laboratory standard and guidelines for population-based cystic fibrosis carrier screening

(Genet Med 3:149-154, 2001) Factor V Leiden Working Group-American College of Medical Genetics consensus statement on Factor V Leiden mutation testing (Genet Med 3:139-148, 2001). Statement on Storage and Use of Genetic Materials Statement on Multiple Marker Screening in Pregnant Women Statement on Use of Apolipoprotein E Testing for Alzheimer Disease. Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents Diagnostic Testing for Prader-Willi and Angelman Syndromes:

Statement on Population Screening for BRCA-1 Mutation in Ashkenazi Jewish Women Principles of Screening: Report of The Subcommittee on Screening of the American

College of Medical Genetics Clinical Practice Committee Position Statement on Carrier Testing for Canavan Disease Statement on Genetic Testing for Cystic Fibrosis Administrative office, 9650 Rockville Pike, Bethesda. MD 20814-3998 ASHI Standards for Molecular Histocompatibility and Immunogenetic Testing

NIH-DOE Task Force on Genetic Testing-Promoting Safe and Effective Genetic testing

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