Quality Assurance Quality Assessment

A quality assurance (QA) program that is established, implemented, and maintained by a laboratory can help ensure high-quality results are provided in clinically relevant turnaround times. Its major goal is to minimize laboratory errors by continual assessment and subsequent improvement of the services provided. Such a program is to cover all steps of the testing operation, including the preanalytical, analytical, and postana-lytical processes, which must be continuously monitored and assessed. A successful QA program should identify and monitor key indicators, preferably of high-risk, high-volume activities, on a regular basis, to assess quality and to detect possible ways to improve processes and/or products. The document describing the policies and procedures of a QA program should contain the elements of why there is a need to assess, what is to be monitored, how and when this is to be done, and by whom. It should also include criteria to assure the competency of the laboratory personnel and provide a means of assessing laboratory activities through proficiency testing and peer review.

2.1. PREANALYTIC PHASE The preanalytical phase of a quality assurance program addresses activities that occur prior to testing the patient's specimen. This phase of the testing process has not received the attention it should. The final rules of the Federal Register (2) state that all laboratories are required to identify ways to monitor, assess, and when indicated, correct problems that might occur when tests are requested and during specimen collection and handling. Thus, a vital link in the quality assurance process is the proper identification of patients and their specimens, because a mistake in either of these areas might affect and subsequently influence test results. Each laboratory, therefore, should establish clearly defined criteria for monitoring the proper collection, labeling, preservation, transportation, and storage of a specimen to be tested as part of their QA program. Included in the program are the reasons for the rejection of an unacceptable specimen and what corrective action is to be taken. A well-designed manual or electronic test request form should be prepared by the laboratory, so as to obtain relevant information required to provide accurate results and appropriate report interpretations. If results are entered into a recording or laboratory information system, the laboratory must ensure the information is correct and provide a system for timely correction of both clerical and analytical errors. There should be written criteria determining whether an informed consent is a requirement for specific molecular assays.

2.1.1. Test Requests Manual or electronic test request forms should be designed to allow for sufficient identification of the patient (name and address, date of birth, gender) and physician (name, address, and phone number), the test(s) requested, and pertinent clinical information. Date and time of collection as well as type of specimen collected should be included. For some assays, such as molecular genetic tests, the requisition might require racial/ethnicity data or a pedigree (e.g., for linkage analysis). Specific requirements for parentage/forensic identity testing can be found in detail by referring to the CAP Molecular Pathology Checklist and the American Association of Blood Banks Standards. Completed manual or electronic test requests must accompany the patient's specimen before a laboratory accession number is assigned. Multiple specimens from the same patient are each to have their own accession number.

One of the important considerations in molecular testing is to ensure that the clinical indications are appropriate for the test requested. This is the responsibility of the laboratory director or other members of the medical laboratory staff. If clarification of a clinical condition or any additional information regarding the test request is required, it is to be discussed with the referring physician. If there is a change in the test requested after consultation, it is to be documented and kept as part of the patient's file.

2.1.2. Specimen Collection and Handling The quality of test results is influenced to a high degree by the proper collection and handling of specimens. Ideally, laboratories should have designated reception areas to ensure that specimens are received and stored to minimize the chances of errors and or mix-ups. Procedures should be in place to include details of proper labeling of specimens, method of collection of specimens from all sources, specimen preservation (especially if processing is delayed), and their proper transportation to the laboratory. The protocols must be consistent with good laboratory practice and in compliance with all relevant safety codes as stipulated by the Occupational Safety and Health Administration (OSHA) and their institution (3,4).

When received in the laboratory, a specimen should have been properly labeled with patient name, a unique identifying number (e.g., medical record), source of specimen, date and time collected. At this time, the accession process begins where the condition of the specimen (sample volume sufficient for analysis, is sample clotted, is container intact), the request form, and the referral data are reviewed for completeness. The date and time of receipt and the laboratory accession number are recorded onto a label firmly attached to each specimen container. If there is insufficient information for the laboratory to uniquely identify the specimen, CLSI recommends that specimens be rejected. However, the sample still could be tested if the demographics are incomplete, provided the information will be obtained by fax or phone in a timely manner. It is advisable that the action taken to obtain required data be documented by laboratory personnel and placed in the patient's file.

In situations where molecular testing laboratories are a part of a hospital-based department or reference laboratory, an accession number specific for molecular tests could be computer generated (8). This molecular accession number and patient name is carried throughout the testing process and helps to reduce transcription errors. Only authorized laboratory personnel will have access to a password-protected computer system and to accession patient information. Folders can be created for each patient, at this time, to include a worksheet specific for the test requested, billing information, and a file card with patient name/accession number/test results/date finalized. These can function as a backup if the computer system should malfunction. The final report and supporting test data will eventually be included in the folder. A log of all accessioned patient specimens that were stored must be maintained to allow prompt retrieval for repeat or additional testing (4).

The proper collection of the patient sample will depend on the clinical diagnosis and the test requested. Molecular analysis of neoplasia, infectious diseases, or genetic disorders require specimens from tumor tissue, body fluids, or any nucleated cells. The use of amplification techniques now renders extremely small samples, such as buccal scrapings, urine specimens, dried blood spots, and thin slices of paraffin-embedded tissue, adequate for testing. Laboratories must have available written requirements for the proper collection of patient specimens. For example, molecular testing of blood and bone marrow samples are to be collected in nuclease-free EDTA or ACD (acid citrate dextrose) tubes, not sodium heparin, to inhibit clotting. Heparin reportedly acts as an inhibitor in amplification assays (9). If a sample is received in a heparinized tube, it is recommended that the white blood cells be separated and washed with a physiological buffer before the nucleic acid extraction. This is especially true for RNA analysis, as heparinized plasma has not proven to be suited for quantitative reverse transcription-polymerase chain reaction (RT-PCR) testing, as exemplified by poor quality results (10). Fresh tissue samples for molecular testing should be frozen soon after collection to prevent DNA degradation and sent to the molecular laboratory immediately. If not frozen, it can be placed in a holding media and stored at 4°C for a maximum of 48 h. Tissues that have been paraffin-embedded or specimens preserved in ethanol are stable at room temperature, with minimal DNA degradation. However, tissues fixed in Zenker's, B5, or Bouin's produce extensive DNA damage, making their use inappropriate for molecular studies.

Blood and bone marrow specimens for DNA analysis, if collected properly, can be stored at 4°C for 3-5 days and still yield high-quality DNA for any amplification assay or Southern blot analysis. Farkas et al. (11) evaluated the quality and stability of DNA within clinical specimens such as blood (white blood cells were isolated before storing) and solid tissue (placenta) when stored at several different temperatures for various lengths of time. It was concluded that leukocytes and solid tissues kept at 4°C or frozen are best for short- to intermediate-term storage. In our laboratory, all blood and body fluid samples are refrigerated upon arrival (usually up to 3 d), whereas tissue is immediately stored at -70°C, until ready for processing.

Specimens for RNA analysis require specific collection and handling conditions. One of the common causes of the failure to obtain results is due to insufficient stabilization of RNA in the specimen prior to dispatch to the laboratory. If chaotropic agents, such as guanidium isothiocyanate, are added immediately after collection, the specimen, under these conditions, can be stored for 7 d at ambient temperature before testing. These agents are known to remove proteins and denaturing RNase, which would otherwise degrade RNA. If these agents are not available, consider freezing the specimen to keep the RNA stable. It has been demonstrated that blood samples requiring RNA testing can be stored at 4°C for up to 48 h if the plasma is separated (12).

2.1.3. Rejection of Specimens Specimen rejection may be justified if there is improper handling or a delay in transportation to the laboratory. Unacceptable specimens for testing would be ones that are received thawed in the laboratory when they should have been kept frozen, collected in the wrong anticoagulant, clotted, contaminated, or contain insufficient quantity. However, sub-optimal collection or storage conditions of patient samples should be reviewed on a case-by-case basis. For example, small, improperly handled specimens may be suitable for amplification assays, yielding interpretable molecular results, but not suitable for Southern blotting where large quantities of high-quality DNA are required. In general, it is left to the discretion of the laboratory staff and director to determine whether or not the specimen should be rejected.

If a specimen is rejected, the laboratory personnel must document the occurrence. The documentation should include the date, time, and condition the specimen was received, notification of the referring physician, and whether another specimen was obtainable. This record is kept in the patient file and documented as part of the QA records.

2.1.4. Informed Consent For some molecular genetic tests, informed consent might be required by federal, state, or local laws before initiating the test. This ensures that the patient voluntarily agrees to testing and has some understanding of the reasons for this test. The level of consent depends on whether the genetic test is used for predictive or diagnostic purposes. The laboratory can be of assistance in determining the appropriate level of informed consent and refer to established guidelines (4). The New York State Department of Health recommends consent from all patients who are having a genetic test; however, the referring physician could sign the test requisition indicating that she/he conveyed the required information to the patient (13).

2.2. ANALYTICAL PHASE In the analytical phase, laboratories performing nonwaived testing must meet applicable requirements as set forth in the CLIA'88 regulations and established by CAP's Laboratory Accreditation Program. Such requirements include the availability of a procedure manual, specimen storage, criteria to obtain accurate and reliable test results, and a system to maintain patient records (2). Particular attention will be given to the following: nucleic acid extraction, contamination affecting amplification assays, use of controls, validation of tests, maintenance of equipment, documentation of competency of personnel, and the laboratory's participation in internal and external assessment programs.

2.2.1. Procedure Manual The procedure manual must contain sufficient details of all laboratory assays written so that qualified laboratory personnel can perform them consistently and accurately. The procedure is to include the principle of the test, pertinent clinical significance, specimen requirements, including collection, storage, preservation, and transportation to laboratory, criteria for specimen acceptability and rejection, the reagents needed, the steps to perform the test, quality control measures, verification ranges, interpretation of results, and references and pretinent notes. The style and format of the procedure manual, noted in the CAP Molecular Pathology Checklist, is at the discretion of the Laboratory Director; however, CLSI provides guidelines in their G6P42-A4 publication (14). Electronic procedure manuals are acceptable as long as they are available to all personnel. They are subject to the same controls as the paper version in that they are to be reviewed annually by the laboratory director (or designee). All new procedures or revisions of existing ones are also to be reviewed by the laboratory director (or designee) prior to implementation. If a procedure is discontinued, a copy, must be maintained for a minimum of 2 yr. The initial date of use and retirement date must be clearly indicated on the procedure.

2.2.2. Nucleic Acid Extraction and Specimen Storage The extraction of nucleic acid, DNA, or RNA, is a crucial part of sample handling. Any errors that occur cannot be rectified at later stages of the testing process. Considerable attention should be given by well-trained technologists to adhering to the procedure at this stage of the assay. Methods that rapidly isolate high-quality DNA suitable for analysis are widely available. Kits exist that provide all the components and procedures necessary for isolating DNA from whole blood, bone marrow samples, cultured cells, and so forth (15). However, automated instruments that extract nucleic acid limit the hands on part of the extraction procedure, thereby reducing the chances that an error will occur during the extraction process.

Once DNA or RNA are extracted, the conditions under which these nucleic acids are stored to prevent any significant loss in quality or quantity is important. This is especially important if they are to be used in other molecular assays or retested. The storage conditions for DNA and RNA differ. DNA can be stored for years if kept at 4°C in a buffered solution, such as Tris-EDTA. Diluting and storing in water will easily degrade DNA after a few weeks and it no longer will be useful for any molecular assay. RNA suspended in water must be frozen at -70°C soon after extraction and can be stored long term as such. Freezing and thawing RNA more than three times affects its stability and recovery (10).

All nucleic acid samples must carry the laboratory's accession number, including the date of preparation. This unique identifier would assist in tracing the sample through the testing procedure. There must be a schedule for retaining nucleic acid specimens as stated in the CAP Molecular Pathology Checklist.

2.2.3. Contamination A major concern for any diagnostic molecular laboratory performing nucleic acid amplification methods is the occurrence of false-positive results due to sample-to-sample contamination of nucleic acid during testing or the "carry-over" of DNA from a previous amplification of the same target. Poor laboratory technique and lack of attention to detail by technologists create situations in which amplified products contaminate areas of the laboratory. To minimize the occurrence of false-positive results, laboratories should implement specific practices and procedures including universal standards. An immediate plan of action when a contamination problem is observed would be to cease all testing, discard potentially contaminated reagents and supplies, and appropriately clean work surfaces and equipment. Testing would only resume if new aliquots or lot numbers of reagents, sterilized glassware, pipette tips, filtered buffers, etc., are available for use. The source of the contamination and the process used in its elemination must be documented and become part of the laboratory's QA program. Avoiding or minimizing laboratory contamination requires an appropriate laboratory design and good laboratory practices.

2.2.3.1. Laboratory design Each laboratory should develop its own unidirectional workflow to avoid the possibility of amplicon contamination. Ideally, a laboratory performing amplification assays should be divided into three separate work areas: (1) a reagent preparation area or room, (2) an area for specimen preparation, and (3) an area for amplification and detection (16).

The reagent preparation area (area 1) must be kept very clean and away from any amplified products or patient specimens. The specimen processing area (area 2) should be located as far away from the amplification and detection area (area 3). This separation reduces the possibility of aerosols from extracted specimens to contaminate amplified products leading to false-positive results. Personnel traveling from the specimen preparation to the reagent preparation or the amplification and detection areas must always change their laboratory coats and gloves. Dedicated laboratory coats should be available when going in and out of each area. Laboratory coats or gloves worn in area 3 must never be worn in areas 1 or 2. Careless adherence to these recommendations can lead to carryover contamination from amplified products. However, with the introduction of commercially licensed tests and newer methodologies, some of the above requirements may be reduced.

Prior to the preparation of a specimen for amplification, bench tops and pipettes are to be wiped down with 10% sodium hypochlorite (bleach) and rinsed with 70% alcohol and water to remove biohazardous agents and extraneous nucleic acids. Contaminating amplicons remaining on workbenches can be destroyed by ultraviolet (UV) irradiation from germicidal bulbs through the creation of thymine dimers resulting in nucleic acid unsuitable for analysis. The use of Class II Biological safety cabinets with UV bulbs and HEPA-filtered air or bench top dead-air boxes with UV light attachments provide a clean dustfree worktop. These units are ideal for areas where specimens are prepared for extraction and where reagents are prepared. The UV light should be turned on at least one-half hour before manipulating any nucleic acid at the workbench and turned off before placing hands in working area.

It is recommended that there be a dedicated set of pipettes with plugged (aerosol-barrier) tips or positive-displacement tips for each of the three areas. The exclusive use of pipettes and tips will eliminate cross-contamination of samples. Prior to use pipette tips can be autoclaved, while pipette barrels, test tube racks, and mini centrifuges wiped with 70% ethanol. They all can remain under the hood when the UV light is on. Equipment such as gel apparatus and combs, centrifuges, microtome blades for cutting paraffin-embedded tissue, etc., should also be cleaned with 70% ethanol to minimize cross contamination.

2.2.3.2. Laboratory practices Reagents used in amplification assays once prepared should be divided into aliquots, and stores in an are separate from where specimens are prepared or amplified. Aliquoting minimizes the number of repeated sampling from the same test tube and reduces the potential for cross-contamination. Lot numbers and stored quantities of reagents should be recorded so that if carry-over does occur the source can be easily identified. All components of an amplification assay, such as dNTPs, primers, buffers, Taq polymerase, and RNAse/DNAse-free water, should be added to the reaction tube in the reagent preparation area and securely capped. Each tube should be capped after the addition of the sample, before proceeding to the next tube. It is recommended that the tubes be subject to a quick centrifugation before uncapping to prevent aerosolization.

Carry-over of nonspecific PCR products can be prevented by chemical modification of amplified fragments. For example, inactivation of an amplified product can be done by substituting dUTP for dTTP, thereby generating uracil-containing fragments in the reaction mixture (17). The bacterial enzyme uracil-N-glycosylase (UNG) is added to the reaction and incubated prior to amplification. All uracil-containing DNA carried over from previous PCR reactions are enzymatically destroyed. Another example that is a major problem in isolating high-quality RNA is contamination by ribonuclease (RNAse). Sources of these highly resistant RNA-degrading enzymes are glassware and the hands of laboratory personnel. The treatment of glassware with an RNAse inhibitor, such as diethylpyrocarbonate (DEPC), followed by autoclaving or baking in a 250°C oven for 4 h will inactivate RNAse. Sterile disposable pipette tips and Eppendorf tubes are reported to be RNAse free, but autoclaving again will further reduce the chances of contamination.

2.2.4. Controls A variety of controls must be included for each test system to ensure that the results obtained are valid. The selection, number, and preparation of controls for procedures involving nucleic acid extraction, restriction enzyme digestion, electrophoresis, etc., are determined by the laboratory. Controls that must be included for each assay system are negative, positive, sensitivity controls and a molecular weight marker.

A negative control, meaning a reagent control to which no template has been added, must be included in every amplification assay. This negative control assesses the quality of the reagents by detecting any contaminant or increased background signal due to a few molecules of contaminating sequences. A positive control, which also contains all reagents required for amplification, provides proof that the assay works and specific evidence of amplification for each mutation or genotype included in the test system. In a Southern blot assay, a gene rearrangement (bands other than germline) must be observed for each restriction enzyme digest. These tests need to be repeated. In RT-RNA assays, a "no reverse transcriptase" control is added each time to the test. If a positive result is observed when reverse transcriptase is omitted from a reaction tube, it indicates that either the reagents or the sample is contaminated. Molecular weight markers used with gel electrophoresis must span the range of expected bands for that specific primer set or probe locus.

Each molecular assay should also incorporate a sensitivity or analytical control to determine the lowest level of an analyte that can be detected by that specific methodology. This sensitivity control is especially important in Southern blot and amplification assays. For the Southern blot technique the sensitivity control corresponds to above 5% of the tumor cell population and is to be included with each electrophoresis run. For amplification assays, a known positive sample for that primer set should be serially diluted to the lowest limit for detection of a monoclonal population and included with each analysis.

To determine whether the nucleic acid is amplifiable, a control using primers directed toward a second target within the DNA template is recommended. A positive result indicates that the template is amplifiable and no reaction inhibitors are present. In some instances, these primers can be incorporated into an assay (multiplexing), saving both time and reagents.

Positive control specimens may not always be readily available for use in various assays. There are a number of sources in which such specimens can be obtained. The American Type Culture Collection (ATCC) and other commercial sources offer many tumor cell lines, DNA, and viruses for purchases. See these websites for details: http://ccr.coriell.org/nigms and www.atcc.org. Other sources for obtaining controls are through interlaboratory exchanges, proficiency testing samples, or patient samples that have been tested in parallel with alternative technology (14). There is a need to establish a disease consortia so that the samples for controls (especially positive ones) can be obtained for testing. The Association for Molecular Pathology (AMP) through its website (www.amp.org) has proven to be a valuable source for technical information and education in the applications of molecular diagnostics and a media for exchange of methodologies and ideas.

2.2.5. Test validation Test validation should be conducted before a new test is introduced for clinical diagnosis. Each laboratory must document that they have validated the tests they are offering. Validation ensures that the test meets acceptable performance standards and is appropriate for the population for whom it is intended. Because requirements for the proper in-house validation of a test are not always clearly defined, the Association for Molecular Pathology (AMP) provides recommendations for in-house development of molecular assays (18) and the College of American Pathologists Molecular Pathology checklist refers to standards for test validation. Under CLIA'88 each laboratory that introduces an FDA-cleared or -approved test must demonstrate that it can obtain performance specifications, such as accuracy and precision, comparable to those established by the manufacturer. The laboratory must verify that the manufacturer's normal values are appropriate for their patient population. Assays developed in-house often use reagents purchased under the analyte-specific reagent (ASR) rule. Before introducing an ASR-based test, the laboratory must establish the following performance characteristics prior to reporting patient test results (2).

• accuracy (verified by using split patient samples with another laboratory already performing the test and by using a recognized national agency that provides proficiency test sample, i.e., CAP)

• precision (can be established by using different levels of controls to determine within-run and between run and total imprecision)

• reportable range of the test results

• reference (normal) ranges

• analytic sensitivity (or lowest detectable limit)

• analytic specificity (the ability of the test to only detect the measurable quantity)

• clinical sensitivity (the percentage of positive tests when the clinical disorder is present)

• clinical specificity (the percentage of negative tests when the clinical disorder is absent)

• the positive predictive value (the likelihood that the clinical disorder is present when the test is positive) and

• the negative predictive value (the likelihood that the clinical disorder is absent when the test is negative).

The actual experiment performed to establish analytical and clinical performance characteristics vary and are dependent on whether it is a qualitative, semiquantitative, or quantitative type of test. Guidance for these experiments/evaluations can be obtained from some of the NCCLS documents (ww.nccls.org) or from the ACMG Standards and Guidelines specifically for molecular technique (3).

Once the test is validated, it is recommended that some general quality assurance parameters be applied. These would include monitoring the effect the test results has no patient care, determining how useful the test results are for clinical management, and determining whether the cost of doing the test justifies the result in saving through more rapid and accurate diagnosis.

2.2.6. Maintenance of Equipment An organized system for maintaining and monitoring all equipment and instruments must be established by the laboratory to check the critical operating characteristics so as to provide consistent and reliable test results. Periodic maintenance and function checks must be done in accordance with the manufacturer's specifications. They are to be documented and kept at the workbench along with any service or repair records. For an instrument without specified function checks it is the laboratory's responsibility to establish maintenance and function checks. This system should be in compliance with CLIA'88 standards [see Standard: Maintenance and function checks 493.1254 in Federal Register (2)] and as stated in the CAP Molecular Pathology Checklist (4).

2.2.7. Competency of Personnel The competency of technologists who perform clinical laboratory tests is to be assessed annually. The Laboratory Director, or designee, selects the process to be measured, indicates the reason for the selection, and describes the details of the task. Evaluation could either entail observing a specific aspect of a laboratory procedure, the operation of an instrument, or important laboratory safety procedures. It could also involve discussions with the technologist regarding a clinical procedure to assess their level of understanding or a review of issues pertaining to the control and prevention of contamination when performing amplification assays in the laboratory. A specific example would be monitoring how a technologist in a molecular laboratory extracts DNA from peripheral blood using a specific manufacturer's kit.

The text of the evaluation should indicate the methodology used and the criteria anticipated for a satisfactory performance. If the competency is less than 100%, an explanation of the problem is to be provided, including any corrective or additional training measures to be implemented within a realistic timeframe. The evaluation is to be documented as well as signed and dated by the evaluator.

2.2.8. Proficiency Testing and Accreditation The goal of proficiency testing (PT) is to evaluate a laboratory's performance compared to other laboratories (its peers) participating in the PT program. It is a process for assessing laboratory performance by which multiple laboratories analyze similar samples that are collected and evaluated by an outside entity (19). All CLIA laboratories performing nonwaived testing must participate in organized PT programs when available. When one does not exist for the test, there should be an external or internal PT program established by the laboratory. Applicable external procedures include the splitting of samples for analyses with a reference or other laboratory certified to perform the test or participating in an ungraded PT program, as organized by the Association for Molecular Pathology. For the internal program, some examples are to retest specimens previously assayed by laboratory personnel using pseudonym identifiers (blind study) or to perform clinical validation by chart review. In the blind-study PT method, the Laboratory Director selects the specimen, evaluates the results, and documents the outcome indicating that it is part of the internal PT program.

The College of American Pathologists requires laboratories to participate in proficiency testing or a CAP-approved program of graded interlaboratory comparison testing as part of its accreditation process. The laboratory must enroll in programs with analytes matching those tests that are performed for clinical testing. For molecular diagnostics, ACMG/CAP provides surveys for Molecular Genetics and Molecular Pathology. The laboratories are sent four to six specimens twice a year for each survey. The survey samples must be integrated within the routine laboratory workload using the same method as for patient samples and rotated among all laboratory personnel. A detailed questionnaire accompanies the samples and is used to record results and interpretation. The results are anonymously reviewed and analyzed. The final graded report, when issued to each of the participants, is an indication of the laboratory's performance compared to other laboratories performing the same procedures using identical or similar methods.

Unacceptable responses might be the result of improper handling of the PT sample, incorrect recording of results, or the incompetency of the testing personnel. Therefore, if an unacceptable result is received by the laboratory, the findings must be evaluated and corrective action taken. This action might entail personnel training and reviewing of test procedures. Both CLIA and CAP require documentation of action of unacceptable results.

Through the PT process, participants can identify procedural problems and take corrective action before patient results are affected. It can be used to document personnel competency and identify problems that might be resolved with additional training and monitoring. Proficiency testing provides continuing medical education for the laboratory.

2.3. POSTANALYTICAL PHASE The postanalytic phase issues involve assuring the accuracy and reliability of test results, reports designed to provide patient laboratory data effectively, and maintain patient confidentiality. The final report should provide an appropriate summary of the methods, the objective findings, and a clinical interpretation. Laboratory test results must be readily available to the laboratory and released to the requesting physician in a timely manner.

2.3.1. Laboratory Test Reports The laboratory report should include the name and address of the patient, a unique patient identifier, name and location of the laboratory, the date the test was performed, and description of the test methodology. The report should also include the source of the specimen and any information regarding the condition of the specimens if it did not meet the laboratory's criteria of acceptance. All laboratory reports must be clear, concise, accurate, and fully interpretative. The results should be brief and unambiguous. If they are complex, results may be presented in table format rather than text form. A statement interpreting the data, including clinical implications, follow-up recommendations, and the limits of the assay, must be written so that it is understandable to a nonmedical professional. The final report is to be signed by the laboratory director or other authorized individual and indicate the date it was finalized.

Molecular testing laboratories must include as part of the report the federally required clarifying statement for tests using analyte-specific reagents. The mandatory language is "This test was developed and its performance characteristics determined by (laboratory name). It has not been cleared or approved by the U.S. Food and Drug Administration." The CAP recommends the addition of "The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes. It should not be regarded as investigational or for research. This laboratory is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA'88) as qualified to perform high complexity clinical laboratory testing" (4). It is our suggestion that FDA approved tests also be recognized as such in final reports.

A copy of the final report, including all supporting test data, are to be kept in the patient's file. Requests for copies to be sent to other health care providers are to documented by a written request from the patient. The reports, when finalized, are often distributed to the requesting physician via standard mail, or fax, or by hand.

Any questionable findings must be resolved by additional analysis (reprobing of blot or digestion of another sample, etc.) before reporting the results to the referring physician. If there is a lack of correlation of molecular results to other laboratory findings, such as histopathologic diagnosis, it is recommended that these cases be investigated to resolve the discrepancies. It could be just a problem with tissue sampling. Guidelines standardizing the reporting of results, interpretations, when to repeat a test, recommendations as to secondary testing, and correlation of results with other clinical data should all be developed as part of the postanalytic quality assurance process.

As per CLSI guidelines (5), all patient laboratory records should be accessible and easily retrieved. They should be cross-referenced by both the patient name and by a second unique identifier (e.g., medical record member or laboratory accession number). The records are retained for a period of time as required by applicable federal or state regulations. CLIA'88 recommends that copies of patient records should be kept for a minimum of 10 yr, or as required by state law (20). Electronic records are acceptable. However, guidelines for specimen retention time have not yet been agreed upon.

2.3.2. Timeliness of Reporting One of the important commitments in a laboratory's operation is providing test results within a time period suitable for prompt patient management decisions. This involves establishing limits for turnaround time (TAT) of tests offered. Turnaround time is defined as the time (e.g., number of hours or days) it takes to issue a result from receipt of the specimen in the laboratory to when the final report is resulted. What is acceptable will depend on the type of sample, the test requested, and the laboratory workload.

It is each laboratory's responsibility to check, at regular intervals, TAT against the threshold set for each of the assays offered. This can be monitored by establishing an indicator that would tabulate the percentage of reports completed by the stated TAT for the test(s). Prolonged TAT is to be investigated and corrective action taken perhaps by improving or changing the methodology. It is the laboratory director's responsibility to monitor TAT, including the volume of samples analyzed to detect trends, systematic errors, or local population variations that might have an effect on tests results or interpretation.

2.3.3. Correction of Errors Despite care and protective measures, errors do occur during the accessioning process. As stated in the CAP Molecular Pathology checklist, there must be a system for timely correction of both clerical and analytical errors. Clerical errors, such as incorrect spelling of a patient's name, incorrect address, wrong medical record number, or wrong date of birth, can occur during the accessioning of a patient specimen or as a result of misinformation provided by the referring clinician. These are to be corrected as soon as they become evident. Errors in the reported test results or misinterpretation of laboratory findings, must be corrected immediately. The referring physician is to be promptly notified and an amended report issued. A copy of this amended report is placed in the patient's file, including documentation of the error and the corrective action taken. To reduce clerical and analytical errors, laboratory results and patient demographics should be checked independently by a qualified member of the laboratory staff prior to signing out of the report by the laboratory director.

Errors occurring during the testing process, such as mislabel-ing a test tube, mixing two different patient specimens, or recording incorrect data on worksheets, must be corrected promptly. The technologist who has made the error(s) must document the event and indicate how it was corrected. In some cases, the test might have to be repeated at the laboratory's expense. In general, identifiable errors must be corrected immediately, because they could later translate into significant problems and potentially compromise the quality of patient care (8).

2.3.4. Patient Confidentiality Records should be maintained in a manner to preserve patient confidentiality. All reports are issued to the referring physician or genetic professional, not the patient. They can be released to other healthcare professionals only with appropriate "authorization for release" from the patient. The laboratory must have a policy in place to protect the confidentiality of the test results reporting. For example, if a request for test results made by telephone from the referring physician's office, the laboratory personnel receiving the call must verify that it is the physician's office calling. The name and telephone number of the caller is obtained and patient's laboratory folder is reviewed to verify this is the referring physician. The event is documented and remains part of the patient file. If discrepancies exist, the matter should be referred to the laboratory director or manager.

Recently, new patient rights and healthcare provider regulations mandated by The Health Insurance Protability & Accountability Act (HIPAA) (21) were instituted. The regulations require all healthcare providers and their staff to restrict the use and disclosure of medical information and provide privacy rights for all their patients. Since each patient has the right to know who has access to and where their test results were sent, laboratories should incorporate into their QA policies how they are maintaining patient confidentiality. In New Jersey, the laboratory is legally required to share certain patient information, outside the realm of treatment, with agencies concerned with payment of services or healthcare, i.e., the New Jersey Department of Health and local health departments, that have not been authorized by the patient. To comply we developed a computer program to allow tracking of this information efficiently upon request of the patient.

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