Draft Genetic Test Review

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Cystic Fibrosis
Clinical Utility

(347KB)

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CLINICAL UTILITY

Question 26: What is the natural history of the disorder?
Question 27: What is the impact of a positive (or negative) test on patient care?
Question 28: If applicable, are diagnostic tests available?
Question 29: Is there an effective remedy or acceptable action, or other measurable benefit?
Question 30: Is there general access to that remedy or action?
Question 31: Is the test being offered to a socially vulnerable population?
Question 32: What quality assurance measures are in place?
Question 33: What are the results of pilot trials?
Question 34: What health risks can be identified for follow-up testing and/or intervention?
Question 35: What are the financial costs associated with testing?
Question 36: What are the economic benefits associated with actions resulting from testing?
Question 37: What facilities/personnel are available or easily put in place?
Question 38: What educational materials have been developed and validated, and which of these are available?
Question 39: Are there informed consent requirements?
Question 40: What methods exist for long term monitoring?
Question 41: What guidelines have been developed for evaluating program performance?

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CLINICAL UTILITY

Question 39: What are the informed consent requirements?

Informed consent for cystic fibrosis prenatal screening is recommended by the American College of Medical Genetics, due to the vulnerability of the screened population (Question 6). In addition, there is no available treatment for cystic fibrosis prenatally. Therefore, the only option available to parents who test positive and wish to avoid the birth of an affected child, is to terminate the pregnancy. Since this option will be morally unacceptable for some, and emotionally difficult for many, it is important that women/couples fully understand the lack of other preventive options before entering the testing pathway. To accomplish this, the health provider or screening program should provide a simple and clear booklet to be given to eligible women/couples at the earliest stages of their pregnancy (Question 8). It is also considered standard of care that a carrier couple who choose to have amniocentesis are offered genetic counseling before the procedure. General recommendations about informed consent for genetic tests vary. New York State regulations that the laboratory make a reasonable effort to document consent prior to testing. This can be in the form of a patient or physician signature. Existing CLIA regulations do not require that laboratories document informed consent, but current CLIAC recommendations do include this requirement. The NCCLS Molecular Guidelines state that the referring clinician has the primary responsibility for informing patients of the risks, costs and benefits of testing. Whether or not the laboratory is required to document consent is left to the discretion of the laboratory and any applicable federal, state or local requirements.

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CLINICAL UTILITY

Question 40: What methods exist for long-term monitoring?

Summary Long-term monitoring helps to document, and ensure, quality of service delivery assess public health impact identify areas of concern The process requires cooperation between health care providers and screening laboratory personnel. Oversight by professional organizations and/or governmental agencies would be beneficial. A successful monitoring strategy involves ensuring that the data collected are useful.

Methods for organizing and conducting a practical evaluation of public health programs have been published (Loc et al., CDC Handbook). Cystic fibrosis screening is now becoming available as part of routine prenatal care. Long term monitoring of the screening process can be valuable in helping to assure quality and assess public health impact. Long term monitoring also provides a framework for the collection of further information about clinical validity and utility, as well as ethical, legal, social and financial issues. Areas of concern in the screening process can also be identified by this mechanism. In conjunction with the introduction of routine screening, decisions should be made as to the questions of interest, as well as the strategies to be employed to collect, analyze and report relevant information. Specific goals could also be established at that time. Priorities for studying long term monitoring issues might be based on feedback from providers, laboratories, and those being offered screening. Stakeholders, including the general pregnancy population, public health officials, cystic fibrosis screening laboratory directors, health care providers, third party payers and advocacy groups are appropriate to include in the process. Long term monitoring can provide answers to the following types of questions:

• Are providers and patients properly educated to make informed decisions?
• Is the quality of laboratory service adequate?
• In aggregate form, what are the results of laboratory testing?
• Is the panel of recommended mutations appropriate?
• How are laboratory test results reported to the provider/patient?
• What actions are taken based on the laboratory results?
• Is there a discernable impact on birth prevalence of cystic fibrosis?
• Is reimbursement being routinely provided?
• Are there further ethical, legal or social implications that need to be addressed?
• Should the screening process be modified or discontinued?

Based on previous collection efforts of this type, long term monitoring data will be most successful when all of those engaged in the effort find the information to be useful. Figure 4-3 shows a schematic of the groups involved in the process. One example of how this could occur in prenatal cystic fibrosis screening is to address the problem of collecting ethnic/racial data on the laboratory requisition slip. This information is necessary for accurate computation of residual risk. In order to encourage the collection of this important information, primary care providers need to be convinced that the laboratory interpretation of test results will take this into account and that their patients will directly benefit. The American College of Obstetricians and Gynecologists (ACOG) could be helpful in informing their membership about this and similar types of issues. The laboratory can then use of this information in its interpretation. Monitoring the racial/ethnic mix of samples arriving for testing could help in ensuring that the test is being offered appropriately. Lastly, those responsible for providing oversight of long term monitoring might periodically survey laboratories and provide feedback and recommendations.

Figure 4-3. A Schematic Representing the Groups Involved In Collecting, Evaluating and Using Long Term Monitoring Information

Laboratory information could be obtained through surveys distributed to participants of external proficiency testing programs (e.g., the ACMG/CAP MGL survey). An existing example of a nationwide survey of this type involves the collection of information concerning prenatal screening for Down syndrome. (Palomaki et al., 1997). Some of the success of this survey was due to ACOG Technical Bulletins directed specifically to this topic, outlining the responsibilities of the primary care provider to supply necessary demographic and pregnancy-related information to the laboratory. Data collection on the part of screening laboratories could also be required as part of the accreditation process by CLIA or CAP, or as part of the proposed FDA review process. There are some types of information that can be gathered without involving laboratories directly. Targeted studies could evaluate specific topics in depth at an individual screening site. Long term monitoring of the birth prevalence could be accomplished by a non-profit organization such as the Cystic Fibrosis Foundation. Much of the needed information is already being collected by that organization. Ethical, legal, and social issues are most appropriately examined by individual studies or surveys. This approach may allow important questions to be answered in the areas of discrimination, stigmatization, and barriers to access. Table 4-1 contains selected data elements, stratified according to screening stage, that could be addressed as part of a long-term monitoring effort.

Table 4-30 presents the data that might be collected by each screening laboratory. The laboratory needs to distinguish whether the sample to be tested is for screening or diagnostic purposes, by including an ‘indication' field on the requisition slip. Examples of indications other than general population screening include: family history of cystic fibrosis, clinical suspicion of cystic fibrosis, and prenatal diagnosis.

Table 4-30. Possible Topics to be Addressed for Prenatal Cystic Fibrosis Screening as Part of a Long Term Monitoring Effort

Pre-analytic

Completeness of patient information on the requisition slip

Sample rejection rate

Indication for testing (restrict to prenatal screening)

Analytic

Number of mutations tested

Assay and test failure rates

Number of women/couples screened

(stratified by race/ethnicity, socioeconomic status, region and gestational age)

Turn-around time

Carrier fequencies (stratified by race/ethnicity)

Partner uptake rates for programs using two-step model (stratified by race/ethnicity)

Number and rate of carrier couples (stratified by race/ethnicity)

Number and rate of affected pregnancies (termination rate optional)

Methods of payment

Post-analytic

Software used and contents of report

Long term knowledge of women/couples

Impact of birth prevalence (stratified by race/ethnicity)

Patient/health care provider satisfaction

Misscellaneous ethical, legal or social issues

 

Table 4-31. Specific Information that a Laboratory Offering Prenatal Screening for Cystic Fibrosis Might Have Available to Satisfy Requests for Long Term Monitoring Information

General Laboratory Information

Completeness of Filing out requisition slips

Sample rejection and assay failure rates

Turn-around time (from arrival to reporting)

Specific Information for Each Woman/Couple Screened

Date of test

Geographic location where the woman's sample was obtained

Race/ehtnicity

Gestational age at initial sampling

Result of test (i.e., positive, negative, failure)

For positive test, the mutation detected

Specific Information for Each Woman/Couple Testing Positive

Whether partner accepted

If yes, partner test result (if positive, mutation detected)

Was genetic counseling offered/accepted

Was prenatal diagnostic testing of the fetus offered/accepted

Results of prenatal diagnostic testing

Date result transmitted to couple

Pregnancy outcome (i.e., termination vs. continuation)

Reference laboratories providing services to distant programs may find it difficult to collect information in the third section of Table 4-31. In some instances, when a woman is found to have a mutation and the partner's sample is requested, that sample may go to another laboratory because of insurance requirements (each partner has a different insurance company that utilizes a different laboratory). This could make identifying positive couples difficult. Further, counseling may be handled locally, and diagnostic testing may be directed to another laboratory. Given the relatively infrequent occurrence of a couple testing positive, methods need to be found to collect this information in order to document whether the screening process is functioning properly. Some laboratories may find it difficult to identify the resources necessary for the data collection. In order to encourage data collection, it is important to provide feedback. For example, The European Quality Assessment Schemes reported that 31 percent of cystic fibrosis reports contained errors (Dequeker et al., 2000). These findings from Europe suggest that it will be important to monitor laboratory reports in the United States, as well. If this were to be done, it could: 1) document the overall status of cystic fibrosis reporting in the United States, 2) identify specific errors that could be corrected, and 3) identify the characteristics of a standard clinical report. Reports from pilot trials (Question 33) contain summaries for much of the laboratory-based information suggested in Table 4-31. However, these reports often leave out crucial details, are active over only a short time period, or cover only a small geographic area. Since prenatal screening for cystic fibrosis is still not widespread in the United States, there have been no comprehensive reports documenting screening services as described in this section.

References:

Dequeker E, Cassiman J. 2001. Genetic proficiency testing in diagnostic laboratories – quality control is the message. Am J Hum Genet 200;67:a274.

Holtzman NA, Watson MS. Final Report of the Task Force on Genetic Testing, Promoting Safe and Effective Genetic Testing in the United States. http://www.nhgri.nih.gov/ELSI/TFGT_final/

Loc, H, Adair S, Mathison, Abedor AJ, Griffin S. Practical Evaluation of Public Health Programs. Public Health Training Network, Centers for Disease Control, Atlanta, Georgia http://www.cdc.gov/phtn/Pract-Eval/workbook.htm

Palomaki GE, Knight GJ, McCarthy JE, Haddow JE, Donhowe JM. 1997. Maternal serum screening for Down syndrome in the United States: A 1995 survey. Am J Obstet Gynecol 176:1046-1051.

Secretary's Advisory Committee on Genetic Testing. Adequacy of Oversight of Genetic Tests. National Institutes of Health, Bethesda, Maryland. http://www4.od.nih.gov/oba/sacgt.htm

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CLINICAL UTILITY

Question 41: What guidelines have been developed for evaluating program performance?

Summary No specific guidelines for long term program evaluation have been published In the absence of guidelines and oversight requirements, it is suspected that many screening laboratories are not collecting the type of information necessary for such monitoring

No specific guidelines for long-term program evaluation of prenatal cystic fibrosis screening have been published. A collaborative effort of the American College of Medical Genetics and American College of Obstetricians and Gynecologists has resulted in clinical and laboratory guidelines for such screening, but these guidelines do not include program evaluation (Grody et al., 2001; Grody and Desnick, 2001). These two organizations are the logical groups to develop cystic fibrosis program evaluation guidelines, or to delegate this task to a third party.

Gap in Knowledge: Guidelines for Long Term Program Evaluation. Currently there are no guidelines for the evaluation of prenatal cystic fibrosis screening programs. Many clinical laboratories providing such services are not collecting the necessary information for an appropriate evaluation.

References:

Grody WW, Desnick RJ. 2002. Cystic fibrosis population carrier screening: here at last – are we ready? Genet Med 3:88-91.

Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, Desnick RJ. 2001. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Genet Med 3:149-154.